Cytoskeletal active compounds, composition and use

ABSTRACT

The present invention is directed to synthetic cytoskeletal active compounds that are related to natural Latrunculin A or Latrunculin B. The present invention is also directed to pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier. The invention is additionally directed to a method of preventing or treating diseases or conditions associated with actin polymerization. In one embodiment of the invention, the method treats increased intraocular pressure, such as primary open-angle glaucoma. The method comprises administering to a subject a therapeutically effective amount of a cytoskeletal active compound of Formula I or II, wherein said amount is effective to influence the cytoskeleton, for example by inhibiting actin polymerization.

This application is a divisional of U.S. application Ser. No.11/950,327, filed Dec. 4, 2007 now U.S. Pat. No. 7,666,861; which is adivisional of U.S. application Ser. No. 11/389,665, filed Mar. 23, 2006,now U.S. Pat. No. 7,320,974; which claims the benefit of U.S.Provisional Application No. 60/665,408, filed Mar. 25, 2005. Thecontents of the above applications are incorporated herein by referencein their entirety.

TECHNICAL FIELD

This invention relates to synthetic cytoskeletal active compounds, suchas latrunculin analog compounds, and the methods of making suchcompounds. The invention also relates to using such compounds in theprevention or treatment of diseases or disorders that are affected bythe integrity of the actin cytoskeleton, for example, treatment ofdisorders in which intraocular pressure is elevated, such as primaryopen-angle glaucoma.

BACKGROUND OF THE INVENTION

Glaucoma is an ophthalmic disease that leads to irreversible visualimpairment. It is the fourth most common cause of blindness and thesecond most common cause of visual loss in the United States, and themost common cause of irreversible visual loss among African-Americans.Generally speaking, the disease is characterized by a progressiveneuropathy caused at least in part by deleterious effects resulting fromincreased intraocular pressure on the optic nerve. In normalindividuals, intraocular pressures ranges from 12 to 20 mm Hg, averagingapproximately 16 mm Hg. However, in individuals suffering from glaucoma,intraocular pressures generally rise above 25 to 30 mm Hg and cansometimes reach 70 mm Hg. Importantly, the loss of vision can resultfrom intraocular pressures only slightly above or even within thestatistically normal range, in eyes which are unusuallypressure-sensitive, over a period of years. Moreover, extremely highpressures (e.g., 70 mm Hg) may cause blindness within only a few days.[See, e.g., P. L. Kaufman and T. W. Mittag, “Medical Therapy OfGlaucoma,” Ch. 9, Sec. II (pp. 9.7-9.30) In P. L. Kaufman and T. W.Mittag (eds.): Glaucoma (Vol. 7 of S. M. Podos and M. Yanoff (eds):Textbook of Opthalmology Series). London, Mosby-Year Book Europe Ltd.(1994); A. C. Guyton, Textbook of Medical Physiology (W. B. SaundersCo., Sixth Ed.), pp. 386-89 (1981)].

Open-angle glaucoma constitutes approximately 90% of all primaryglaucomas and is characterized by abnormally high resistance to fluid(aqueous humor) drainage from the eye. Normal resistance is required tomaintain an intraocular pressure sufficient to maintain the shape of theeye for optical integrity. This resistance is provided by the trabecularmeshwork, a complex tissue consisting of specialized endothelial cells,connective tissue beams and extracellular matrix. The resistance of thetrabecular meshwork normally is such that intraocular pressure is ˜16 mmHg, a pressure at which aqueous humor leaves the eye at the same rate atwhich it is produced (2.5 μL/minute).

Typical treatments for glaucoma comprise a variety of pharmaceuticalapproaches for reducing intraocular pressure (IOP) to normal levels.Beta-blockers and carbonic anhydrase inhibitors only reduce aqueoushumor production, which is needed to nourish the avascular lens andcorneal endothelial cells, and the prostaglandins effect is on theuvealscleral outflow pathway, which only accounts for 10% of the totalfacility. There are currently no commercially approved therapeuticagents which act directly upon the trabecular meshwork, the site ofincreased resistance to aqueous humor outflow and thus responsible forelevated IOP. Therefore, a medical need remains for improvedIOP-lowering medications that target this structure. Pharmacologicalagents which target the trabecular meshwork may provide relief to thesignificant numbers of patients that do not respond adequately tocurrent IOP-lowering medications and/or cannot tolerate the side effectsassociated with these agents.

U.S. Pat. Nos. 6,586,425; 6,110,912; and 5,798,380 disclose a method forthe treatment of glaucoma using compounds that affect the actin filamentintegrity of the eye to enhance aqueous humor outflow. These patentsalso specifically disclose kinase inhibitors and latrunculin-A,latrunculin-B, swinholide-A, and jasplakinolide, which cause aperturbation of the actin cytoskeleton in the trabecular meshwork or themodulation of its interactions with the underlying membrane.Perturbation of the cytoskeleton and the associated adhesions reducesthe resistance of the trabecular meshwork to fluid flow and therebyreduces intraocular pressure.

Trabeculectomy is the most common form of glaucoma filtration surgeryand remains as the first-line therapy for surgical reduction ofpharmacologically uncontrolled intraocular pressure in primary openangle glaucoma. This procedure establishes a limbal fistula throughwhich aqueous humor drains into the subconjunctival space establishing afiltering bleb to lower intraocular pressure. The success of theprocedure is highly dependent on pharmacological modulation of woundhealing.

A major advance in the surgical management of glaucoma has been the useof antimetabolites to prevent scarring after glaucoma filtrationsurgery. Postoperative scarring of the filtering bleb is the mostcrucial factor in determining the short and long-term outcome of modernglaucoma filtration surgery. The antimetabolites mitomycin C (MMC) and5-fluorouracil (5-FU) are the most widely used to suppress scarring andthus failure of the filtering bleb. In a large retrospective study,conventionally performed trabeculectomy, has shown a failure rate of upto 30% within 3 months after surgery. To lower the incidence of thisdetrimental complication, various methods have been investigated inorder to avoid the naturally occurring scarring of the filtering bleb,mostly dealing with the intraoperative or postoperative application ofantimetabolic drugs—that is, 5-fluorouracil (5-FU) or mitomycin C (MMC),the two most widely used cytotoxic agents.

Despite their positive long-term effect on prolonged filtration, theapplication of cytotoxic drugs to a surgically opened eye increases theincidence of severe complications such as concomitant increases invision threatening complications. MMC exhibits a high incidence ofsevere post-application complications as does 5-FU although its sideeffects mainly affect the corneal epithelium and its clinical use islimited by severe pain and discomfort to the patient. No sufficientmethod has been established to achieve satisfying postoperative longterm surgical results with only minimal or no side effects for thepatient.

There exists a need for effective and cost-practical cytoskeletal activecompounds to treat glaucoma, to modulate wound healing aftertrabeculectomy, and to treat other diseases or disorders that areaffected by the integrity of the actin cytoskeleton. Naturallatrunculins, cytoskeletal active macrolides harvested and isolated frommarine sponges such as Latrunculia magnifica, Negombata magnifica, andSpongia mycofijiensis, and from nudibranches, for example Chromodorislochi, are difficult to obtain a large quantity. Latrunculin analogscurrently can only be prepared using lengthy, low-yielding, andimpractical syntheses (A. B. Smith III et al., J. Am. Chem. Soc. 1992,114, 2995-3007; J. D. White and M. Kawasaki, J. Org. Chem. 1992, 57,5292-5300; A. Fürstner et al., Angew. Chem. Int. Ed. 2003, 42,5358-5360; A. Fürstner et al., Proc. Natl. Acad. Sci. 2005, 102,8103-8108). There exists a need for novel cytoskeletal active compoundsthat can be prepared using simple and practical synthetic procedures.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula I or FormulaII, which are analogs related to the natural products latrunculin A orlatrunculin B. The present invention is also directed to pharmaceuticalcompositions comprising such compounds and a pharmaceutically acceptablecarrier.

The invention is additionally directed to a method of preventing ortreating diseases or conditions associated with actin polymerization. Inone embodiment of the invention, the method treats increased intraocularpressure, such as primary open-angle glaucoma.

The method comprises administering to a subject a therapeuticallyeffective amount of a cytoskeletal active compound of Formula I or II,wherein said amount is effective to alter the actin cytoskeleton, suchas by inhibiting actin polymerization.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention have discovered compounds thatare cytoskeletal active agents, which modify the actin cytoskeleton, forexample by inhibiting actin polymerization. The compounds describedherein bear a relationship to the natural products latrunculin A and B.These compounds contain structural simplifications that result in someaspects of their preparation being more practical, thus they arepractical to be used as therapeutic agents. The structural modificationsdescribed herein provide new analogs with therapeutic utility.

Definitions

When present, unless otherwise specified, the following terms aregenerally defined as, but are not limited to, the following:

Halo substituents are taken from fluorine, chlorine, bromine, andiodine.

Alkyl groups are from 1 to 12 carbon atoms inclusively, either straightchained or branched, are more preferably from 1 to 8 carbon atomsinclusively, and most preferably 1 to 6 carbon atoms inclusively.

Alkylene chains are from 2 to 20 carbon atoms inclusively, have twopoints of attachment to the to the molecule to which they belong, areeither straight chained or branched, can contain one or more doubleand/or triple bonds, are more preferably from 4 to 18 atoms inclusively,and are most preferably from 6 to 14 atoms inclusively.

Alkenyl groups are from 1 to 12 carbon atoms inclusively, eitherstraight or branched containing at least one double bond but can containmore than one double bond.

Alkynyl groups are from 1 to 12 carbon atoms inclusively, eitherstraight or branched containing at least one triple bond but can containmore than one triple bond, and additionally can contain one or moredouble bonded moieties.

“Alkoxy” refers to the group alkyl-O— wherein the alkyl group is asdefined above including optionally substituted alkyl groups as alsodefined above.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to14 carbon atoms inclusively having a single ring (e.g., phenyl) ormultiple condensed rings (e.g., naphthyl or anthryl). Preferred arylsinclude phenyl, naphthyl and the like.

“Arylalkyl” refers to aryl-alkyl-groups preferably having from 1 to 6carbon atoms inclusively in the alkyl moiety and from 6 to 10 carbonatoms inclusively in the aryl moiety. Such arylalkyl groups areexemplified by benzyl, phenethyl and the like.

“Arylalkenyl” refers to aryl-alkenyl-groups preferably having from 1 to6 carbon atoms in the alkenyl moiety and from 6 to 10 carbon atomsinclusively in the aryl moiety.

“Arylalkynyl” refers to aryl-alkynyl-groups preferably having from 1 to6 carbon atoms inclusively in the alkynyl moiety and from 6 to 10 carbonatoms inclusively in the aryl moiety.

“Aryloxy” refers to the group aryl-O— wherein the aryl group is asdefined above including optionally substituted aryl groups as alsodefined above.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 12 carbon atomsinclusively having a single cyclic ring or multiple condensed ringswhich can be optionally substituted with from 1 to 3 alkyl groups. Suchcycloalkyl groups include, by way of example, single ring structuressuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl,1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and thelike, or multiple ring structures such as adamantyl, and the like.

“Cycloalkenyl” refers to cyclic alkenyl groups of from 4 to 12 carbonatoms inclusively having a single cyclic ring or multiple condensedrings and at least one point of internal unsaturation, which can beoptionally substituted with from 1 to 3 alkyl groups. Examples ofsuitable cycloalkenyl groups include, for instance, cyclobut-2-enyl,cyclopent-3-enyl, cyclooct-3-enyl and the like.

“Cycloalkylalkyl” refers to cycloalkyl-alkyl-groups preferably havingfrom 1 to 6 carbon atoms inclusively in the alkyl moiety and from 6 to10 carbon atoms inclusively in the cycloalkyl moiety. Suchcycloalkylalkyl groups are exemplified by cyclopropylmethyl,cyclohexylethyl and the like.

“Heteroaryl” refers to a monovalent aromatic carbocyclic group of from 1to 10 carbon atoms inclusively and 1 to 4 heteroatoms inclusivelyselected from oxygen, nitrogen and sulfur within the ring. Suchheteroaryl groups can have a single ring (e.g., pyridyl or furyl) ormultiple condensed rings (e.g., indolizinyl or benzothienyl).

“Heteroarylalkyl” refers to heteroaryl-alkyl-groups preferably havingfrom 1 to 6 carbon atoms inclusively in the alkyl moiety and from 6 to10 carbon atoms inclusively in the heteroaryl moiety. Such arylalkylgroups are exemplified by pyridylmethyl and the like.

“Heteroarylalkenyl” refers to heteroaryl-alkenyl-groups preferablyhaving from 1 to 6 carbon atoms inclusively in the alkenyl moiety andfrom 6 to 10 carbon atoms inclusively in the heteroaryl moiety.

“Heteroarylalkynyl” refers to heteroaryl-alkynyl-groups preferablyhaving from 1 to 6 carbon atoms inclusively in the alkynyl moiety andfrom 6 to 10 carbon atoms inclusively in the heteroaryl moiety.

“Heterocycle” refers to a saturated or unsaturated group having a singlering or multiple condensed rings, from 1 to 8 carbon atoms inclusivelyand from 1 to 4 hetero atoms inclusively selected from nitrogen, sulfuror oxygen within the ring. Such heterocyclic groups can have a singlering (e.g., piperidinyl or tetrahydrofuryl) or multiple condensed rings(e.g., indolinyl, dihydrobenzofuran or quinuclidinyl). Preferredheterocycles include piperidinyl, pyrrolidinyl and tetrahydrofuryl.

Examples of heterocycles and heteroaryls include, but are not limitedto, furan, thiophene, thiazole, oxazole, pyrrole, imidazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,indole, indazole, purine, quinolizine, isoquinoline, quinoline,phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline,pteridine, carbazole, carboline, phenanthridine, acridine,phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,pyrrolidine, indoline and the like.

Positions occupied by hydrogen in the foregoing groups can be furthersubstituted with substituents exemplified by, but not limited to,hydroxy, oxo, nitro, methoxy, ethoxy, alkoxy, substituted alkoxy,fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, alkyl,substituted alkyl, thio, thioalkyl, acyl, carboxyl, alkoxycarbonyl,carboxamido, substituted carboxamido, alkylsulfonyl, alkylsulfinyl,alkylsulfonylamino, sulfonamido substituted sulfonamide, cyano, amino,substituted amino, acylamino, trifluoromethyl, trifluoromethoxy, phenyl,aryl, substituted aryl, pyridyl, imidazolyl, heteroaryl, substitutedheteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloalkyl, substituted cycloalkyl, pyrrolidinyl, piperidinyl,morpholino, and heterocycle; and preferred heteroatoms are oxygen,nitrogen, and sulfur. It is understood that where open valences exist onthese substituents they can be further substituted with alkyl,cycloalkyl, aryl, heteroaryl, and/or heterocycle groups, and wheremultiple such open valences exist, these groups can be joined to form aring, either by direct formation of a bond or by formation of bonds to anew heteroatom, preferably oxygen, nitrogen, or sulfur. It is furtherunderstood that the above substitutions can be made provided thatreplacing the hydrogen with the substituent does not introduceunacceptable instability to the molecules of the present invention, andis otherwise chemically reasonable.

Pharmaceutically acceptable salts are salts that retain the desiredbiological activity of the parent compound and do not impart undesiredtoxicological effects. Pharmaceutically acceptable salt foams includevarious polymorphs as well as the amorphous form of the different saltsderived from acid or base additions. The acid addition salts can beformed with inorganic or organic acids. Illustrative but not restrictiveexamples of such acids include hydrochloric, hydrobromic, sulfuric,phosphoric, citric, acetic, propionic, benzoic, napthoic, oxalic,succinic, maleic, malic, adipic, lactic, tartaric, salicylic,methanesulfonic, 2-hydroxyethanesulfonic, toluenesulfonic,benzenesulfonic, camphorsulfonic, and ethanesulfonic acids. Thepharmaceutically acceptable base addition salts can be formed with metalor organic counterions and include, but are not limited to, alkali metalsalts such as sodium or potassium; alkaline earth metal salts such asmagnesium or calcium; and ammonium or tetraalkyl ammonium salts, i.e.,NX₄ ⁺ (wherein X is C₁₋₄).

Tautomers are compounds that can exist in one or more forms, calledtautomeric forms, which can interconvert by way of a migration of one ormore hydrogen atoms in the compound accompanied by a rearrangement inthe position of adjacent double bonds. These tautomeric forms are inequilibrium with each other, and the position of this equilibrium willdepend on the exact nature of the physical state of the compound. It isunderstood that where tautomeric forms are possible, the currentinvention relates to all possible tautomeric forms.

Solvates are addition complexes in which a compound of Formula I or IIis combined with a pharmaceutically acceptable cosolvent in some fixedproportion. Cosolvents include, but are not limited to, water, methanol,ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol, tert-butanol,acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, benzene,toulene, xylene(s), ethylene glycol, dichloromethane,1,2-dichloroethane, N-methylformamide, N,N-dimethylformamide,N-methylacetamide, pyridine, dioxane, and diethyl ether. Hydrates aresolvates in which the cosolvent is water. It is to be understood thatthe definition of compounds in Formulae I and II encompasses allpossible hydrates and solvates, in any proportion, which possess thestated activity.

Novel Compounds

The cytoskeletal active compounds useful for this invention includecompounds of general Formulae I and II, and/or tautomers thereof, and/orpharmaceutically-acceptable salts, and/or solvates, and/or hydratesthereof.

A compound according to Formulae I and II can exist in severaldiastereomeric forms. The general structure of Formulae I and IIincludes all diastereomeric forms of such materials, when not specifiedotherwise. Formulae I and II also include mixtures of compounds of theseFormulae, including mixtures of enantiomers, diastereomers and/or otherisomers in any proportion.

A. Formula I

Compounds of Formula I are as follows:

wherein:

-   -   X₁=S, O, NR₃, or CR₄R₅;    -   Y₁=S, O, or NR₆;    -   Y₂=S, O, or NR₇;    -   Z₁=S, O, NR₈, or absent;    -   Q₁ and Q₂ are independently O or S;    -   A₁ and A₂ are independently hydrogen, halo, alkyl, or alkoxy,        optionally substituted;    -   n=1, 2, or 3;    -   R₁-R₈ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,        arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl,        heteroarylalkynyl, orheterocycle, optionally substituted;    -   the dashed line indicates that unsaturation is allowed in the        ring containing it;    -   with the first proviso that when Z₁=S or O; R₂ is not H;    -   with the second proviso that when n is 1, X₁ is S, Y₁ is NR₆, Y₂        is O, Z₁ is absent, Q₁ and Q₂ are O, and if R₂ is selected from        one of the following groups:        -   methyl,

-   -   -   -   (Z)-5-acetoxy-2-methylpent-1-en-1-yl, or

-   -   -   -   (Z)-5-hydroxy-2-methylpent-1-en-1-yl;

    -   then R₁ is not 3-monomethyl-substituted alkyl, or R₁ is not        selected from among the following groups:

-   -   (S,4Z,6E,10Z)-11-methoxycarbonyl-3,10-dimethylundeca-4,6,10-trien-1-yl,

-   -   -   (S,Z)-6-acetoxy-3-methylhex-4-en-1-yl,

-   -   -   (S,Z)-6-hydroxy-3-methylhex-4-en-1-yl, or

-   -   -   -   (S)-4-acetoxy-3-methylbutyl;                where in these structures, the bond marked with an arrow                denotes the point of attachment of the group R₁ or R₂ to                the rest of the molecule.

In one embodiment of Formula I, A₁ and A₂ are both hydrogen, and thering containing X₁ is fully saturated, which is described by Formula Ia.

with the remaining Formula Ia substituents as defined above for FormulaI.

In Formulae I and Ia, the preferred X₁ is S, O, or NR₃, the morepreferred X₁ is S, the preferred Y₁ is NR₆, the more preferred Y₁ is NH,the preferred Y₂ is O or NR₇, the more preferred Y₂ is O, the preferredZ₁ is absent, the preferred Q₁ and Q₂ are O, the preferred n is 1 or 2,the more preferred n is 1, the preferred R₁ and R₂ are alkenyl,cycloalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl,and heteroarylalkenyl, in which both R₁ and R₂ are independently between2 and 16 atoms, and both are optionally substituted, and the morepreferred R₁ and R₂ are alkenyl, cycloalkenyl, aryl, arylalkenyl,heteroaryl, and heteroarylalkenyl, in which both R₁ and R₂ areindependently between 4 and 12 atoms, and both are optionallysubstituted.

A preferred Formula I and Formula Ia compound is wherein:

-   -   X₁=S, O, or NR₃;    -   Y₁=NR₆;    -   Y₂=O or NR₇;    -   Z₁=absent;    -   Q₁ and Q₂ are O;    -   A₁ and A₂ are independently hydrogen, halo, alkyl, or alkoxy,        optionally substituted;    -   n=1 or 2;    -   R₁ and R₂ are independently H, alkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl,        arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl,        heteroarylalkenyl, heteroarylalkynyl, or heterocycle, optionally        substituted; and    -   R₃-R₈ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, or cycloalkylalkyl;    -   with the second proviso as stated above.

A more preferred Formula I and Formula Ia compound is wherein:

-   -   X₁=S;    -   Y₁=NH;    -   Y₂=O or NR₇;    -   Z₁=absent;    -   Q₁ and Q₂ are O;    -   A₁ and A₂ are independently hydrogen, halo, alkyl, or alkoxy,        optionally substituted;    -   n=1;    -   R₁ and R₂ are independently H, alkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl,        arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl,        heteroarylalkenyl, heteroarylalkynyl, or heterocycle, optionally        substituted; and    -   R₃-R₈ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, or cycloalkylalkyl;    -   with the second proviso as stated above.

In one embodiment of the invention, a Formula I and Formula Ia compoundis wherein:

-   -   X₁=S, O, NR₃, or CR₄R₅;    -   Y₁=S, O, or NR₆;    -   Y₂=S, O, or NR₇;    -   Z₁=S, O, NR₈, or absent;    -   Q₁ and Q₂ are independently O or S;    -   A₁ and A₂ are independently hydrogen, halo, alkyl, or alkoxy,        optionally substituted;    -   n=1, 2, or 3;    -   R₁-R₈ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,        arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl,        heteroarylalkynyl, or heterocycle, optionally substituted;    -   the dashed line indicates that unsaturation is allowed in the        ring containing it;    -   with a first proviso that when Z₁=S or O, R₂ is not H;    -   with a second proviso that when n=1, X₁ is S, Y₁ is NR₆, Y₂ is        O, Z₁ is absent, Q₁ is O, and Q₂ is O,    -   and in the case that R₁ is optionally substituted alkyl or        alkenyl and begins with CH₂CH₂ from the point of attachment to        the pyran ring, then R₁ is:

-   -   where the bond marked with an arrow denotes the point of        attachment of the group R₁ to the rest of the molecule,    -   wherein R₉-R₁₀ are independently H, halo, alkyl, or alkenyl,        optionally substituted, and R₁₁ is H, halo, alkyl, alkenyl, or        —W—R₁₂, optionally substituted, where    -   W=O, S, SO, SO₂, NH, or N-alkyl, and    -   R₁₂ is H, alkyl, or alkenyl,    -   provided that if R₉ is H and R₁₀ is methyl, then R₁₁ is H, halo,        or —W—R₁₂.

Specific Compounds illustrative of Formula I and Formula Ia are shown inthe following Compounds 1-7. In the following structures, hydrogens areomitted from the drawings for the sake of simplicity. Tautomers drawnrepresent all tautomers possible. Structures are drawn to indicate thepreferred stereochemistry; where diastereomers may be generated in thesecompounds, structures are taken to mean any of the possiblediastereomers alone or a mixture of diastereomers in any ratio.

(Z)-((2R,4R,6R)-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate

(Z)-N-((2R,4R,6R)-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)-3-methylhepta-2,6-dienamide

(Z)-((2R,4R,6R)-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-pentyl-tetrahydro-2H-pyran-4-yl)3-methylhept-2-enoate

(2R,4R,6R)-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl3-methylbut-2-enoate

(2R,4R,6R)-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-ylbenzoate

(2R,4R,6R)-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl4-methoxybenzoate

(2R,4R,6R)-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl4-(methylsulfonyl)benzoate

(Z)-((2R,4R,6R)-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate

(2R,4R,6R)-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl3-methylbut-2-enoate

(2R,4R,6R)-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-ylbenzoate

(2R,4R,6R)-6-ethyl-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-tetrahydro-2H-pyran-4-ylbenzoate

B. Formula II

Compounds of Formula II are as follows:

wherein:

-   -   R_(a) is an alkylene chain, from 4 to 15 atoms in length,        wherein the carbon atoms of the alkylene chain are optionally        replaced by from 1 to 3 O, S, or N atoms, wherein the alkylene        chain optionally contains from 1 to 4 unsaturations, 1 to 2        cycloalkyl, 1 to 2 aryl, 1 to 2 heteroaryl, or 1 to 2        heterocycle rings, and is optionally substituted;    -   X₁=S, O, NR₃, or CR₄R₅;    -   Y₁=S, O, or NR₆;    -   Y₂=S, O, or NR₇;    -   Z₁=S, O, NR₈, or absent;    -   Q₁ and Q₂ are independently O or S;    -   A₁ and A₂ are independently hydrogen, halo, alkyl, or alkoxy,        optionally substituted;    -   n=1, 2, or 3;    -   R₃-R₈ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,        arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl,        heteroarylalkynyl, or heterocycle, optionally substituted;    -   the dashed line indicates that unsaturation is allowed in the        ring containing it;    -   with the proviso that when n is 1, X₁ is S, Y₁ is NR₆, Y₂ is O,        Z₁ is absent, and Q₁ and Q₂ are O, then either R_(a) is not        3-monomethyl-substituted, as counted from the point of        attachment distal to Z₁; or R_(a) is not selected from the        following groups:

(S,1Z,5Z)-2,7-dimethylnona-1,5-diene-1,9-diyl,

(S,1Z,5E,7Z)-2,9-dimethylundeca-1,5,7-triene-1,11-diyl,

(S,1Z,7Z)-2,9-dimethylundeca-1,7-diene-1,11-diyl, or

(S,1Z,7Z)-2,9-dimethyl-5,6-epoxyundeca-1,7-diene-1,11-diyl;

where in these structures the right-most bond marked with an arrowindicates the point of attachment of R_(a) to Z₁, and the left-most bondmarked with an arrow indicates the point of attachment of R_(a) to thepyran ring of Formula II.

In one embodiment of Formula II, A₁ and A₂ are both hydrogen, and thering containing X₁ is fully saturated, which is described by FormulaIIa.

with the remaining Formula IIa substituents as defined above for FormulaII.

In Formulae II and IIa, in the description of R_(a), the terms“optionally containing cycloalkyl, aryl, heteroaryl, or heterocyclerings” indicate replacement of any carbon-carbon bond in R_(a) with acycloalkyl, aryl, heteroaryl, or heterocycle ring. Examples of suchreplacements include, but are not be limited to, the replacement of acarbon-carbon single, double, or triple bond with 1,2-cyclopentyl,1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl,1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridyl, 2,4-pyridyl,3,5-pyridyl, and 2,3-tetrahydrofuranyl.

In Formulae II and IIa, the preferred X₁ is S, O, or NR₃, the morepreferred X₁ is S, the preferred Y₁ is NR₆, the more preferred Y₁ is NH,the preferred Y₂ is O or NR₇, the more preferred Y₂ is O, the preferredZ₁ is absent, the preferred Q₁ and Q₂ are O, the preferred n is 1 or 2,the more preferred n is 1, the preferred R_(a) is an alkylene chain,from 6 to 13 atoms in length, wherein a carbon atom of the alkylenechain is optionally replaced by 1 O, S, or N atom, wherein the alkylenechain optionally contains from 1 to 3 unsaturations, and is optionallysubstituted, and the more preferred R_(a) is an alkylene chain, from 8to 11 atoms in length, wherein the alkylene chain optionally containsfrom 1 to 3 unsaturations, and is optionally substituted.

A preferred Formula II and Formula IIa compound is wherein:

-   -   R_(a) is an alkylene chain, from 6 to 13 atoms in length,        wherein a carbon atom of the alkylene chain is optionally        replaced by 1 O , S, or N atom, wherein the alkylene chain        optionally contains from 1 to 3 unsaturations, and is optionally        substituted;    -   X₁=S, O, or NR₃;    -   Y₁=NR₆;    -   Y₂=O or NR₇;    -   Z₁=absent;    -   Q₁ and Q₂ are O;    -   A₁ and A₂ are independently hydrogen, halo, alkyl, or alkoxy,        optionally substituted;    -   n=1 or 2; and    -   R₃-R₈ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, or cycloalkylalkyl;    -   with the same proviso as stated above.

A more preferred Formula II and Formula IIa compound is:

-   -   R_(a) is an alkylene chain, from 8 to 11 atoms in length,        wherein the alkylene chain optionally contains from 1 to 3        unsaturations, and is optionally substituted;    -   X₁=S;    -   Y₁=NH;    -   Y₂=O or NR₇;    -   Z₁=absent;    -   Q₁ and Q₂ are O;    -   A₁ and A₂ are independently hydrogen, halo, alkyl, or alkoxy,        optionally substituted;    -   n=1;    -   R₃-R₈ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, or cycloalkylalkyl;    -   with the same proviso as stated above.

In one embodiment of the invention, a Formula II and Formula IIacompound is wherein:

-   -   X₁=S, O, NR₃, or CR₄R₅;    -   Y₁=S, O, or NR₆;    -   Y₂=S, O, or NR₇;    -   Z₁=absent;    -   Q₁ and Q₂ are independently O or S;    -   A₁ and A₂ are independently hydrogen, halo, alkyl, or alkoxy,        optionally substituted;    -   n=1, 2, or 3;    -   R₃-R₈ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,        arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl,        heteroarylalkynyl, or heterocycle, optionally substituted;    -   R_(a) is:        (CH₂)_(m1)—(CR₉R₁₀)—(CH₂)_(m2)—V₁—(CH₂)_(m3)—V₂    -   wherein:        -   m₁, m₂, and m₃ are independently 0-5 inclusively, and            m₁+m₂+m₃ is between 2 and 14 inclusively;        -   R₉ and R₁₀ are independently H, halo, alkyl, alkenyl,            alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl,            arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl,            heteroarylalkenyl, heterocycle, or —W—R₁₂, optionally            substituted;        -   W=O, S, SO, SO₂, NH, N-alkyl, N-cycloalkyl, N-aryl, or            N-heteroaryl;        -   R₁₂ is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl;        -   V₁ is NR₁₃, O, S, SO, SO2, cis —C(R₁₃)═C(R₁₄)—, trans            —C(R₁₃)═C(R₁₄)—, —C-(triple bond)-C—, —OC(═O)—, —C(═O)O—,            —N(R₁₃)C(═O)—, —C(═O)N(R₁₃)—, —N(R₁₃)C(═O)O—,            —OC(═O)N(R₁₃)—, —N(R₁₃)SO2—, —SO2N(R₁₃)—,            —N(R₁₃)C(═O)N(R₁₄)—, cycloalkyl, cycloalkenyl, aryl,            heteroaryl, heterocycle, or absent;        -   V₂ is NR₁₃, O, cis —C(R₁₃)═C(R₁₄)—, trans —C(R₁₃)═C(R₁₄)—,            —C-(triple bond)-C—, cycloalkyl, cycloalkenyl, aryl,            heteroaryl, heterocycle, or absent;        -   R₁₃ and R₁₄ are independently H, alkyl, alkenyl, alkynyl,            cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl,            arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl,            or heterocycle, optionally substituted;

with the proviso that when m₁ is 2, m₂ is 0, m₃ is 2, V₁ is cis —CH═CH—,V₂ is —C(Me)═CH—, R₉ is H, and R₁₀ is alkyl,

then R₁₀ has at least 2 carbon atoms (e.g. C₂-C₁₀ alkyl, preferablyC₂-C₆ alkyl).

In the above embodiment, the preferred X₁ is S, O, or NR₃, the morepreferred X₁ is S, the preferred Y₁ is NR₆, the more preferred Y₁ is NH,the preferred Y₂ is O or NR₇, the more preferred Y₂ is O, the preferredQ₁ and Q₂ are O, the preferred n is 1 or 2, the more preferred n is 1,

-   the preferred R₃-R₈ are independently H, alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl,    arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl,    optionally substituted, the more preferred R₃-R₈ are H, alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkylalkyl,    optionally substituted;-   the preferred m₁, m₂, and m₃ are 0-4 inclusively, the more preferred    m₁, m₂, and m₃ are 0-3, inclusively;-   the preferred R₉ and R₁₀ are independently H, halo, alkyl, alkenyl,    cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl,    heteroaryl, heteroarylalkyl, or —W—R₁₂, optionally substituted, the    more preferred R₉ and R₁₀ are H, halo, alkyl, alkenyl, cycloalkyl,    cycloalkenyl, cycloalkylalkyl, aryl, or arylalkyl, optionally    substituted;-   the preferred W=O, S, NH, N-alkyl, N-cycloalkyl, N-aryl, or    N-heteroaryl, the more preferred W=O, S, NH, N-alkyl, or    N-cycloalkyl;-   the preferred R₁₂ is H, alkyl, alkenyl, cycloalkyl, aryl, or    heteroaryl, the more preferred R₁₂ is H, alkyl, cycloalkyl, or aryl;-   the preferred V₁ is NR₁₃, O, S, cis —C(R₁₃)═C(R₁₄)—, trans    —C(R₁₃)═C(R₁₄)—, N(R₁₃)C(═O)—, —C(═O)N(R₁₃)—, —N(R₁₃)C(═O)O—,    —OC(═O)N(R₁₃)—, cycloalkyl, cycloalkenyl, aryl, heteroaryl,    heterocycle, or absent, the more preferred V₁ is O, S, cis    —C(R₁₃)═C(R₁₄)—, trans —C(R₁₃)═C(R₁₄)—, cycloalkyl, aryl, or absent;-   the preferred V₂ is NR₁₃, cis —C(R₁₃)═C(R₁₄)—, trans    —C(R₁₃)═C(R₁₄)—, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or    absent, the more preferred V₂ is cis —C(R₁₃)═C(R₁₄)—, trans    —C(R₁₃)═C(R₁₄)—, cycloalkenyl, or aryl;-   the preferred R₁₃ and R₁₄ are H, alkyl, alkenyl, cycloalkyl,    cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,    heteroaryl, heteroarylalkyl, or heteroarylalkenyl, optionally    substituted, the more preferred R₁₃ and R₁₄ are H, alkyl,    cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl, or    heteroaryl, optionally substituted.

In one embodiment of the invention, a Formula II and Formula IIacompound is wherein:

-   -   R_(a) is an alkylene chain, from 4 to 15 atoms in length,        wherein the carbon atoms of the alkylene chain are optionally        replaced by from 1 to 3 O, S, or N atoms, wherein the allylene        chain optionally contains from 1 to 4 unsaturations, 1 to 2        cycloalkyl, 1 to 2 aryl, 1 to 2 heteroaryl, or 1 to 2        heterocycle rings, and is optionally substituted;    -   X₁=S, O, NR₃, or CR₄R₅;    -   Y₁=S, O, or NR₆;    -   Y₂=S, O, or NR₇;    -   Z₁=S, O, NR₈, or absent;    -   Q₁ and Q₂ are independently O or S;    -   A₁ and A₂ are independently hydrogen, halo, alkyl, or alkoxy,        optionally substituted;    -   n=1, 2, or 3;    -   R₃-R₈ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,        arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl,        heteroarylalkynyl, or heterocycle, optionally substituted;    -   the dashed line indicates that unsaturation is allowed in the        ring containing it;    -   with the proviso that when n is 1, X₁ is S, Y₁ is NR₆, Y₂ is O,        Z₁ is absent, Q₁ is O, Q₂ are O,    -   and in the case that R_(a) is 9 or 11 carbons in length, begins        with CH₂CH₂ from the point of attachment to the pyran ring, and        does not contain aryl or heteroaryl, then R_(a) is:    -   then R_(a) is:

-   -   wherein R_(b) is an alkylene chain, C₆-C₈ in length, optionally        containing from 1 to 4 unsaturations, optionally containing a        cycloalkyl ring and optionally substituted, and R₉ and R₁₀ are        independently H, halo, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,        heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocycle, or        —W—R₁₂, optionally substituted, where        -   W=O, S, SO, SO₂, NH, N-alkyl, N-cycloalkyl, N-aryl, or            N-heteroaryl, and        -   R₁₂ is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl,    -   such that if R₉ is H, and R₁₀ is alkyl, then R₁₀ has at least 2        carbon atoms (e.g. C₂-C₁₀ alkyl, preferably C₂-C₆ alkyl);

where in this structure the right-most bond marked with an arrowindicates the point of attachment of R_(a) to Z₁, and the left-most bondmarked with an arrow indicates the point of attachment of R_(a) to thepyran ring of Figure II.

Specific compounds illustrative of Formula II are shown in the followingCompounds 8-27. In the following structures, hydrogens have been omittedfrom the drawings for the sake of simplicity. Tautomers drawn representall tautomers possible. Structures are drawn to indicate the preferredstereochemistry; where diastereomers may be generated in thesecompounds, structures are taken to mean any of the possiblediastereomers alone or a mixture of diastereomers in any ratio.

(R)-4-((1R,4Z,8Z,13R,15R)-15-hydroxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)thiazolidin-2-one

(R)-4-((1R,4Z,8E,13R,15R)-15-hydroxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)thiazolidin-2-one

(R)-4-((1R,4Z,8E,10S,13R,15R)-15-hydroxy-5,10-dimethyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)thiazolidin-2-one

(1R,4Z,8Z,13R,15R)-15-hydroxy-5-methyl-15-((R)-2-oxothiazolidin-4-yl)-14-oxa-2-aza-bicyclo[11.3.1]heptadeca-4,8-dien-3-one

(1R,13R,15R,Z)-15-hydroxy-15-((R)-2-oxothiazolidin-4-yl)-4,14-dioxa-2-aza-bicyclo[11.3.1]heptadec-8-en-3-one

(R)-4-((1R,4Z,8E,10Z,15R,17R)-17-hydroxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadeca-4,8,10-trien-17-yl)thiazolidin-2-one

(R)-4-((1R,13R,15R,Z)-15-hydroxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-4-en-15-yl)thiazolidin-2-one

(R)-4-((1R,13R,15R,Z)-15-hydroxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-8-en-15-yl)thiazolidin-2-one

(R)-4-((1R,13R,15R)-15-hydroxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadecan-15-yl)thiazolidin-2-one

(R)-4-((1R,14R,16R,E)-16-hydroxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadec-9-en-16-yl)thiazolidin-2-one

(R)-4-((1R,14R,16R)-16-hydroxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadecan-16-yl)thiazolidin-2-one

(R)-4-((1R,15R,17R,Z)-17-hydroxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadec-4-en-17-yl)thiazolidin-2-one

(S)-4-((1R,4Z,8Z,13R,15R)-15-hydroxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)oxazolidin-2-one

(S)-4-((1R,4Z,8Z,10S,13R,15R)-15-hydroxy-5,10-dimethyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-1,3-thiazinan-2-one

4-((1R,4Z,8Z,13R,15R)-15-hydroxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-1-methyl-1H-imidazol-2(3H)-one

(R)-4-((1R,4Z,8Z,10S,13R,15R)-5-ethyl-15-hydroxy-10-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)thiazolidin-2-one

(R)-4-((1R,4Z,8Z,10S,13R,15R)-15-hydroxy-4,5,10-trimethyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)thiazolidin-2-one

(R)-4-((1R,11Z,13S,16R,18R)-18-hydroxy-13-methyl-3-oxo-2,17-dioxatricyclo[14.3.1.0^(4,8)]icosa-4(8),11-dien-18-yl)thiazolidin-2-one

(R)-4-((1R,12Z,14S,17R,19R)-19-hydroxy-14-methyl-3-oxo-2,18-dioxatricyclo[15.3.1.0^(4,9)]henicosa-4,6,8,12-tetraen-19-yl)thiazolidin-2-one

(R)-4-((1R,10Z,15R,17R)-17-hydroxy-3-oxo-2,16-dioxatricyclo[13.3.1.1^(4,8)]icosa-4(20),5,7,10-tetraen-17-yl)thiazolidin-2-one

(R)-4-((1R,4Z,8Z,10S,13R,15R)-10-ethyl-15-hydroxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)thiazolidin-2-one

(R)-4-((1R,4Z,8Z,13R,15R)-15-hydroxy-5,10,10-trimethyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)thiazolidin-2-one

(R)-4-((1R,4S,13Z,17R,19R)-19-hydroxy-4,13-dimethyl-15-oxo-16,20-dioxatricyclo[15.3.1.0^(5,10)]henicosa-5,7,9,13-tetraen-19-yl)thiazolidin-2-one

(R)-4-((1R,4S,12Z,16R,18R)-18-hydroxy-4,12-dimethyl-14-oxo-15,19-dioxa-6-thiatricyclo[14.3.1.0^(5,9)]icosa-5(9),7,12-trien-18-yl)thiazolidin-2-one

(R)-4-((1R,15E,19R,21R)-21-hydroxy-15-methyl-17-oxo-18,22-dioxa-8-azatricyclo[17.3.1.0^(5,10)]tricosa-5,7,9,15-tetraen-21-yl)thiazolidin-2-one

(1R,13R,15R)-8-acetyl-15-hydroxy-15-((R)-2-oxothiazolidin-4-yl)-2,14-dioxa-8-aza-bicyclo[11.3.1]heptadecan-3-one

(R)-4-((1R,10S,13R,15R)-15-hydroxy-10-methyl-3-oxo-2,8,14-trioxa-bicyclo[11.3.1]heptadecan-15-yl)thiazolidin-2-one

(R)-4-((1R,13R,15R)-15-hydroxy-3-oxo-2,14-dioxa-9-thia-bicyclo[11.3.1]heptadecan-15-yl)thiazolidin-2-one

Preparation of Compounds of Formula I and Formula II

The present invention is additionally directed to procedures forpreparing compounds of Formulae I and II. General approaches forpreparations of the compounds of Formulae I and II are described inSchemes 1 and 2. Those having skill in the art will recognize that thestarting materials can be varied and additional steps can be employed toproduce compounds encompassed by the present invention. In some cases,protection of certain reactive functionalities may be necessary toachieve some of the above transformations. In general, the need for suchprotecting groups as well as the conditions necessary to attach andremove such groups will be apparent to those skilled in the art oforganic synthesis.

Those skilled in the art will recognize various synthetic methodologiesthat can be employed to prepare non-toxic pharmaceutically acceptableprodrugs, for example acylated prodrugs, of the compounds of thisinvention.

The preparation of materials described by Formula I is shown inScheme 1. In this Scheme, an acyl compound bearing a chiral auxiliary(1.1) is reacted in an aldol condensation with an aldehyde to yield analdol product (1.2). This aldol condensation may be carried out usingtitanium enolate conditions; alternatively, other aldol conditions suchas lithium or boron enolate or Mukaiyama aldol conditions may be used.This aldol reaction provides stereoisomers, which may be separated atthis point. The aldol product is protected, typically with anacid-labile protecting group such as a silyl protecting group, to yieldthe protected aldol (1.3). Reduction of this protected compound,typically with diisobutylaluminum hydride (DIBAL-H), provides thealdehyde (1.4). Protected heterocyclic ketones 1.5 are prepared usingmethods analogous to those reported by Smith et al. (A. B. Smith III etal., J. Am. Chem. Soc. 1992, 114, 2995-3007), or more preferably using amethod in which the protecting group “Pg” is introduced in a two stepcondensation-reduction sequence, followed by cyclization to foam theheterocyclic ring and elaboration of the ketone moiety, as describedbelow in Examples 1 through 5. Aldol reaction of aldehyde 1.4 with theheterocyclic ketone 1.5, under aldol conditions such as titanium,lithium, or boron enolate conditions or Mukaiyama aldol conditions,gives the aldol product (1.6). This aldol may yield diastereomericproducts, which may be separated at this point in the synthesis or atlater points. Removal of the protecting group “Pg”, typically bytreatment with mild acid, provides the deprotected material (1.7), asthe hemiketal. Under some conditions, the protecting group is removeddirectly in the aldol reaction during the reaction itself or during itsworkup. This material is protected as the ketal (1.8), typically themethyl ketal, by treatment with an alcohol and acid, typically asulfonic acid, optionally in the presence of a cosolvent. The compounds1.7 and 1.8 provide convenient points for the separation ofstereoisomers in some cases. The alcohol 1.8 is converted to the ester(1.9) either by direct acylation, such as with a carboxylic acid and asuitable activating agent such as a carbodiimide or carbonyldiimidazole,or by acylation with an acid halide, or by an inversion process such asby a Mitsunobu reaction or by preparation of an active leaving groupsuch as a sulfonate ester and displacement with a suitably activatedform of a carboxylic acid nucleophile. Final deprotection of the ester1.9 provides compound 1.10, an example of the substances described byFormula I. It will be seen that modifications of this synthetic schemeusing well-known procedures will allow the preparation of other membersin the scope of Formula I.

The preparation of materials described by Formula II is shown in Scheme2. In this Scheme, a compound of general form 2.1 is prepared using themethods described in Scheme 1. In this compound, the substituents“R_(x)” and “R_(y)” are substituents that bear functionality that willallow a macrocyclization reaction to take place, yielding a macrocycle(2.2) with a newly foamed substituent “R_(a)” incorporated in the newring. Suitable macrocyclization reactions in this case include, forexample, ring forming metathesis reactions, olefination, lactonization,lactamization, etherification, and amination reactions. Deprotection ofthe macrocyclic compound gives compound 2.3, an example of thesubstances described by Formula II. In an alternative method, a compoundof general form 2.4, also prepared using the methods described in Scheme1, is elaborated using one of the same reactions listed above formacrocyclization to yield a non-macrocyclic precursor (2.5). Theprotecting group “Pg″” is then removed from 2.5 and the resultingproduct is cyclized, for example using a macrolactonization reaction, toprovide compound 2.2, which is deprotected as was previously described.It will be seen that modifications of this synthetic scheme using othersuitable procedures will allow the preparation of other members in thescope of Formula II.

Pharmaceutical Composition and Use

The present invention also provides novel pharmaceutical compositions.The pharmaceutical compositions are pharmaceutically acceptableformulations comprising a pharmaceutically acceptable carrier and one ormore compounds of Formulae I and II, pharmaceutically-acceptable salts,solvates, and/or hydrates thereof. The pharmaceutically acceptablecarrier can be selected by those skilled in the art using conventionalcriteria. Pharmaceutically acceptable carriers include, but are notlimited to, saline and aqueous electrolyte solutions, water polyetherssuch as polyethylene glycol, polyvinyls such as polyvinyl alcohol andpovidone, cellulose derivatives such as methylcellulose andhydroxypropyl methylcellulose, petroleum derivatives such as mineral oiland white petrolatum, animal fats such as lanolin, polymers of acrylicacid such as carboxypolymethylene gel, vegetable fats such as peanut oiland polysaccharides such as dextrans, and glycosaminoglycans such assodium hyaluronate and salts such as sodium chloride and potassiumchloride.

In one embodiment of the invention, the compositions are formulated astopical ophthalmic suspensions or solutions, with a pH of about 4-9,preferably 5 to 8. The compounds of the invention are generallycontained in these formulations in an amount of at least 0.001 or 0.005%by weight, for example, 0.001% to 5% by weight, preferably about 0.01%to about 2% by weight, with an amount of about 0.03% to about 1% byweight being most preferred. For topical administration, one to twodrops of these formulations are delivered to the surface of the eye oneto four times per day according to the routine discretion of a skilledclinician.

In one embodiment of the invention, the compositions are formulated asaqueous pharmaceutical formulations comprising at least one compound ofFormula I or II in an amount of 0.001-2% w/v, and a tonicity agent tomaintain a tonicity between 200-400 mOsm/kG, wherein the pH of theformulation is 4-8, and the formulation does not contain a substantialamount of dimethyl sulfoxide. As used herein, “a substantial amount”refers to more than 0.1%, preferably 0.01%, and more preferably 0.001%.The aqueous pharmaceutical formulation of the present invention does notcontain more than 0.1%, preferably not more than 0.01%, and morepreferably not more than 0.001% v/v of DMSO. In a preferred embodiment,the aqueous pharmaceutical formulation of the present invention does notcontain any dimethyl sulfoxide.

In one embodiment, the aqueous pharmaceutical formulation comprises atleast one compound of Formula I or II in an amount of 0.001-2% w/v,1-100 mM buffer suitable to maintain the pH between 4-6, 0.01-2%surfactant, and a tonicity agent to maintain a tonicity between 200-400mOsm/kG. A preferred buffer is citrate buffer. Preferred tonicity agentsare mannitol and dextrose.

In another embodiment, the aqueous pharmaceutical formulation comprisesat least one compound of Formula I or II in an amount of 0.001-2% w/v,5-10% ethanol and a tonicity agent to maintain a tonicity between200-400 mOsm/kG. The formulation optionally comprises 1-100 mM buffer tomaintain the pH between 4-8.

In yet another embodiment, the aqueous pharmaceutical formulationcomprises at least one compound of Formula I or II in an amount of0.001-2% w/v, 1-10% polypropylene glycol, 0.02-0.25% polaxamer, 0.1-1%polysorbate, and a tonicity agent to maintain a tonicity between 200-400mOsm/kG, wherein the pH of the formulation is 4-8.

In yet another embodiment, the aqueous pharmaceutical formulationcomprises at least one compound of Formula I or II in an amount of0.001-2% w/v, a cyclodextrin, 0.01-0.5% preservative, and a tonicityagent to maintain a tonicity between 200-400 mOsm/kG, wherein the pH ofthe formulation is 4-8.

Glaucoma is an ophthalmic disease that leads to irreversible visualimpairment. Open-angle glaucoma is characterized by abnormally highresistance to fluid (aqueous humor) drainage from the eye. Adhesionsbetween cells of the trabecular meshwork are major determinants of theresistance to flow. The compounds of the present invention in generalcause a transient, pharmacological perturbation of cell adhesions,mainly via disruption of the associated cytoskeletal structures or themodulation of their interactions with the membrane. Perturbation ofthese adhesions reduces the resistance of the trabecular meshwork tofluid flow and thereby reduces intraocular pressure in a therapeuticallyuseful manner.

The compounds of the present invention are useful for modulation ofwound healing after trabeculectomy. The compounds in general are lesstoxic to corneal endothelial cells than the antimetabolites such as5-fluorouracil or mitomycin C. The compounds inhibit actomyosin-drivencontractility, leading to deterioration of the actin microfilamentsystem and perturbation of its membrane anchorage, which weakens thecell-extracellular matrix adhesions. These properties inhibit woundhealing and thereby reduce bleb failure following the surgery.

Angiogenesis is characterized by the development of new vasculature frompre-existing vessels and plays a central role in physiological processessuch as embryogenesis, wound healing and female reproductive function,as well as pathophysiologic events including cancer, rheumatoidarthritis and diabetic retinopathy. The growth and metastasis of tumorsis critically dependent upon angiogenesis. Angiogenesis is a multistepprocess involving the endothelial cell (EC) cytoskeleton in migration,proliferation, and barrier stabilization. Applicants believe thatinteractions between the cytoskeleton and apoptosis are involved in theintracellular pathways by which angiogenic tube formation occurs. Thecompounds of the present invention are useful in inhibiting angiogenesisand treating tumors.

Antimitotic drugs markedly interfere with antidiuretic response,strongly implying that cytoskeleton integrity is essential to thisfunction. This role of the cytoskeleton in controlling the epithelialtransport is a necessary step in the translocation of the water channelcontaining particle aggregates and in their delivery to the apicalmembrane. Regulation of the actin cytoskeleton is important in themodulation of fluid transport. Osmolality-dependent reorganization ofthe cytoskeleton and expression of specific stress proteins areimportant components of the regulatory systems involved in theadaptation of medullary cells to osmotic stress. The compounds of thepresent invention are useful in directing epithelial function andmodulating fluid transport.

The present invention provides a method of reducing intraocularpressure, a method of treating glaucoma, a method of inhibiting woundhealing after trabeculectomy, a method of inhibiting angiogenesis, amethod of treating cancer, and a method of directing epithelial functionand modulating fluid transport. The method comprises the step ofadministering to a subject in need of treatment a pharmaceuticalcomposition comprising a compound of Formula I or Formula II, in anamount effective to alter the actin cytoskeleton, such as by inhibitingactin polymerization.

In one embodiment, the pharmaceutical composition of the presentinvention is administered locally to the eye (e.g., topically,intracamerally, or via an implant) in the form of ophthalmicformulations. The compounds of the invention can be combined withopthalmologically acceptable preservatives, surfactants, viscosityenhancers, penetration enhancers, buffers, sodium chloride, and water toform an aqueous or oily, sterile ophthalmic suspension or solution toform the compositions of the invention.

The active compounds disclosed herein can be administered to the eyes ofa patient by any suitable means, but are preferably administered byadministering a liquid or gel suspension of the active compound in theform of drops, spray or gel. Alternatively, the active compounds can beapplied to the eye via liposomes. Further, the active compounds can beinfused into the tear film via a pump-catheter system. Anotherembodiment of the present invention involves the active compoundcontained within a continuous or selective-release device, for example,membranes such as, but not limited to, those employed in the Ocusert™System (Alza Corp., Palo Alto, Calif.). As an additional embodiment, theactive compounds can be contained within, carried by, or attached tocontact lenses that are placed on the eye. Another embodiment of thepresent invention involves the active compound contained within a swabor sponge that can be applied to the ocular surface. Another embodimentof the present invention involves the active compound contained within aliquid spray that can be applied to the ocular surface. Anotherembodiment of the present invention involves an injection of the activecompound directly into the lacrimal tissues or onto the eye surface.

In addition to the topical administration of the compounds to the eye,when the present compounds are used in a method of inhibitingangiogenesis, a method of treating cancer, or a method of directingepithelial function and modulating fluid transport, the compounds can beadministered systematically by any methods known to a skilled person.

The compounds of the present invention can also be used to treat asthma,COPD, emphysema, bladder dysfunction, and high blood pressure by meansand route of administration known to those skilled in the art. Furtheruses of the present compounds can be in the area of cosmetics forreducing wrinkles, in the area of preserving blood platelets, and in thearea of vasospasm and smooth muscle spasm by means and route ofadministration known to those skilled in the art.

The invention is illustrated further by the following examples that arenot to be construed as limiting the invention in scope to the specificprocedures described in them.

EXAMPLES Example 1

(4R)-2-(4-Methoxyphenyl)thiazolidine-4-carboxylic Acid

A 22 L three-necked round bottom flask fitted with an internaltemperature probe and a mechanical stirrer was charged with L-cysteinehydrochloride monohydrate (500.0 g, 2.85 mol), sodium acetate (260.0 g,3.17 mol) and water (4 L). The mixture was stirred until all of theL-cysteine dissolved. A solution of 4-methoxybenzaldehyde (426.0 g, 3.13mol) in ethanol (3.5 L) was prepared and added to the reaction dropwisesuch that the internal reaction temperature was kept below 30° C. Thereaction went from a clear solution to a thick white slurry during theaddition of the 4-methoxybenzaldehyde solution. After 30 minutes,ethanol (3.5 L) was added to the reaction and the slurry thickened.Stirring was continued for 1 hour and then the solid was isolated byfiltration, and the solid was washed with additional ethanol. The solidwas dried in a vacuum oven at 50° C. over 48 hours to afford the titlecompound (610 g, 90%).

¹H NMR (DMSO, 300 MHz): δ 3.16-3.00 (m, 2H), 3.37-3.23 (m, 2H), 3.71 (s,3H), 3.73 (s, 3H), 3.84 (dd, J=7.6, 7.1 Hz, 1H), 4.23 (dd, J=6.7, 4.4Hz, 1H), 5.42 (s, 1H), 5.56 (s, 1H), 6.93-6.83 (m, 4H), 7.41-7.31 (m,4H).

Example 2

(R)-3-Mercapto-2-(4-methoxybenzylamino)propanoic Acid

A 22 L three-necked round bottom flask fitted with an internaltemperature probe and a mechanical stirrer was charged with sodiumborohydride (221.3 g, 5.85 mol). Aqueous sodium hydroxide (1.75 L, 0.25M) was added and the mixture was stirred until homogeneous. The solutionwas cooled to 0-5° C. The title compound from Example 1 (350.0 g, 1.46mol) was dissolved in aq K₂CO₃ (2.1 L, 0.62 M). This solution was addedto the solution of sodium borohydride over 1 h while stirring. Thetemperature of the reaction was kept below 30° C. during the addition.The reaction was stirred for an additional 1 h period, at which timeHPLC analysis showed no remaining starting material. The reaction wascooled to 0° C. and glacial acetic acid (700 mL) was added dropwise withgentle constant stirring (CAUTION: The reaction mixture becomes foamyand evolves gas, and may overflow the reaction flask if acetic acid isnot added slowly). The final pH of the reaction mixture was 5. The whitesolid was collected by filtration, washed with water and ethanol, anddried in a vacuum oven at 50° C. overnight to afford the title compound(240 g, 68%).

¹H NMR (DMSO, 300 MHz): δ 2.76 (d, J=5.7 Hz, 2H), 3.24 (dd, J=5.3, 5.3Hz, 1H), 3.72 (s, 3H), 3.87 (AB, J_(AB)=13.1 Hz, Δν_(AB)=18.5 Hz, 2H),6.91 (d, 8.9 Hz, 2H), 7.32 (d, 8.9 Hz, 2H).

Example 3

(R)-3-(4-Methoxybenzyl)-2-oxothiazolidine-4-carboxylic Acid

A 22 L three-necked round bottom flask fitted with an internaltemperature probe and a mechanical stirrer was charged with the titlecompound from Example 2 (400.0 g, 1.66 mol), K₂CO₃ (480.0 g, 3.47 mol)and water (2.8 L). The mixture was heated at 40° C. while stirring untilit became homogeneous and was then cooled to room temperature. Asolution of N,N-carbonyldiimidazole (400.0 g, 222.47 mol) inacetonitrile (2.8 L) was added dropwise at a rate that maintained aninternal reaction temperature less than 30° C. The reaction wasmonitored by HPLC and was complete upon the disappearance of thestarting material (about 15 minutes). The acetonitrile was removed byheating at 40° C. and 80-100 torr. Isopropyl acetate (200 mL) was addedand the pH of the mixture was adjusted to 2 with 3 M H₂SO₄. The biphasicmixture was filtered, and the organic phase was isolated. Additionalisopropyl acetate was added and the solution was dried by azeotropicdistillation. The reaction volume was reduced further until aprecipitate began to form. The yellow precipitate was isolated byfiltration and dried at 50° C. overnight to afford the title compound(310 g, 70%).

¹H NMR (DMSO, 300 MHz): δ 3.36-3.28 (m, 1H), 3.67-3.59 (m, 1H), 3.71 (s,3H), 4.31-4.24 (m, 1H), 4.52 (AB, J_(AB)=15.5 Hz, Δν_(AB)=238.4 Hz, 2H),6.88 (d, 8.3 Hz, 2H), 7.15 (d, 8.3 Hz, 2H).

Example 4

(R)-N-Methoxy-3-(4-methoxybenzyl)-N-methyl-2-oxothiazolidine-4-carboxamide

A 22 L three-necked round bottom flask fitted with an internaltemperature probe and a mechanical stirrer was charged with the titlecompound from Example 3 (310.0 g, 1.16 mol) and isopropyl acetate (2.4L). The vessel was purged with nitrogen and cooled to 0° C.N-methylmorpholine (130.0 g, 1.29 mol) was added dropwise such that theinternal reaction temperature never increased above 5° C. The reactionbecame cloudy. Pivaloyl chloride (150.0 g, 1.24 mol) was added dropwisesuch that the internal reaction temperature never increased above 5° C.The reaction was stirred at 0° C. for 45 minutes. N-methoxy-methanamine(78.0 g, 1.28 mol) was added dropwise, again keeping the internalreaction temperature below 5° C. The reaction was monitored by HPLC andwas worked up when the ratio of the product to starting material was 4:1(approximately 30 minutes after amine addition). The mixture was thenwashed with 0.1 M HCl and satd aq NaHCO₃. The organic phase wasseparated and concentrated to a final volume of 1.0 L by distillation.Upon stirring, a precipitate began to form. A 250 mL portion ofn-heptane was added, and the mixture was stirred vigorously. The solidwas filtered and dried in a vacuum oven at 40° C. to afford the titlecompound (250 g, 70%).

¹H NMR (DMSO, 300 MHz): δ 3.15 (dd, J=11.0, 5.5 Hz, 1H), 3.21 (s, 3H),3.38 (s, 3H), 3.46 (dd, J=11.0, 8.5 Hz, 1H), 3.79 (s, 3H), 4.40 (dd,J=8.8, 5.2 Hz, 1H), 4.49 (AB, J_(AB)=14.4 Hz, Δν_(AB)=387.9 Hz, 2H),6.86 (d, 8.9 Hz, 2H), 7.15 (d, 8.9 Hz, 2H).

Example 5

(R)-4-Acetyl-3-(4-methoxybenzyl)thiazolidin-2-one

A dry three-necked round bottom flask fitted with an internaltemperature probe and a mechanical stirrer was charged with a solutionof methylmagnesium chloride in THF (0.805 L, 3 M). The solution waspurged with nitrogen and cooled to 0° C. In a separate flask, the titlecompound from Example 4 (250.0 g, 0.805 mol) was dissolved in dry THF(1.0 L). This solution was added to the solution of methylmagnesiumchloride at a rate that maintained an internal reaction temperature lessthan 5° C. The reaction was monitored by HPLC and was complete upon thedisappearance of the starting material (approx. 20 minutes aftercompleting the addition). The reaction mixture was slowly added into a10% citric acid solution (1 L) at a rate that maintained a temperatureof less than 25° C. The mixture was diluted with water, and the THF wasremoved by distillation at 70° C. (80° C. external) and 1 atm. Theproduct was extracted with ethyl acetate, and the organic phase wasseparated and concentrated by distillation at 76° C. (95° C. external)and 1 atm to a final volume of ˜800 mL. The solution was allowed to coolto room temperature, and n-heptane was added to give a precipitate. Thesuspension was stirred for 30 minutes, and the solid was isolated byfiltration and dried in a vacuum oven at 40° C. overnight to afford thetitle compound (170 g, 80%).

¹H NMR (DMSO, 300 MHz): δ 2.19 (s, 3H), 3.37 (dd, J=11.8, 2.6 Hz, 1H),3.62 (dd, J=11.9, 10.0 Hz, 1H), 3.72 (s, 3H), 4.27 (AB, J_(AB)=15.2 Hz,Δν_(AB)=267.3 Hz, 2H), 4.48 (dd, J=9.4, 2.6 Hz, 1H), 6.88 (d, 8.9 Hz,2H), 7.14 (d, 8.9 Hz, 2H).

Example 6

(R)-3-Hydroxy-1-((R)-4-isopropyl-2-thioxothiazolidin-3-yl)oct-7-en-1-one

A solution of (R)-1-(4-isopropyl-2-thioxothiazolidin-3-yl)ethanone (11.8g, 58.1 mmol) in dichloromethane (380 mL) under an atmosphere ofnitrogen was cooled to −78° C., titanium tetrachloride (6.37 mL, 58.1mmol) was added, and the mixture was stirred for 10 min.Diisopropylethylamine (10.12 mL, 58.1 mmol) was added, and the mixturewas stirred for 1 h at −78° C. A 1 M solution of hex-5-enal (58.1 mL,58.1 mmol) in dichloromethane was added, and the mixture was stirred for2 h at −78° C. The reaction was quenched by addition of half-saturatedNH₄Cl (30 mL) and warmed to room temperature. The mixture was extractedtwice with dichloromethane, and the organic phase was dried andevaporated to provide a residue. Chromatography on silica gel affordedthe title compound (12.92 g, 74%). This procedure has also been carriedout using the (R)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanoneauxiliary, with a similar result.

Example 7

(R)-1-((R)-4-Isopropyl-2-thioxothiazolidin-3-yl)-3-(triethylsilyloxy)oct-7-en-1-one

The title compound from Example 6 (4.27 g, 14.2 mmol) was dissolved inDMF (28 mL) under an atmosphere of nitrogen, and diisopropylethylamine(4.94 mL, 28.3 mmol) was added. The mixture was cooled to 0° C., andtriethylsilyl chloride (2.57 mL, 14.9 mmol) was added. After stirringfor 30 min at 0° C., an additional portion of diisopropylethylamine(1.48 mL, 8.50 mmol) and triethylsilyl chloride (0.73 mL, 4.25 mmol) wasadded, and the mixture was stirred for 1 h. The mixture was poured onto10% aq citric acid and extracted with 1:9 ethyl acetate/hexanes. Theorganic phases were dried and evaporated, and the residue was filteredthrough a silica plug to provide the title compound (6.08 g, 100%).

¹H NMR (CDCl₃, 300 MHz): δ 0.60 (q, 6H), 0.92 (t, 9H), 0.96 (d, 3H),1.08 (d, 3H), 1.64 (m, 4H), 2.04 (m, 2H), 2.40 (sept, 1H), 3.04 (d, 1H),3.16 (dd, 1H), 3.40-3.60 (m, 2H), 4.32 (m, 1H), 4.92-5.08 (m, 3H), 5.80(m, 1H).

Example 8

(R)-3-(Triethylsilyloxy)oct-7-enal

The title compound from Example 7 (6.08 g, 14.2 mmol) was dissolved intoluene (70 mL) under an atmosphere of nitrogen and the mixture wascooled to −78° C. DIBAL (1 M in hexane, 32 mL, 32 mmol) was added over10 min, and the mixture was stirred at −78° C. for 30 min. The reactionmixture was poured onto half-saturated sodium potassium tartratesolution at 0° C. and stirred for 3 h. The phases were separated and theaqueous phase was extracted twice with 1:9 ethyl acetate/hexanes. Thecombined organic phases were dried and evaporated, and the residue wasdiluted with hexane. The resulting solid was filtered off and thefiltrate was concentrated and filtered through a silica plug to providethe title compound (3.40 g, 93%) as an oil.

¹H NMR (CDCl₃, 300 MHz): δ 0.60 (q, J=8 Hz, 6H), 0.95 (t, J=8 Hz, 9H),1.39-1.47 (m, 2H), 1.51-1.63 (m, 2H), 2.05 (q, J=7 Hz, 2H), 2.52 (m,2H), 4.20 (quint, J=6 Hz, 1H), 4.95-5.04 (m, 2H), 5.78 (m, 1H), 9.81 (t,J=2 Hz, 1H).

Example 9

(R)-4-((2R,4R,6R)-2,4-Dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneand(R)-4-((2R,4S,6R)-2,4-Dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

A solution of the product of Example 5 (4.98 g, 18.8 mmol) indichloromethane (60 mL) under a nitrogen atmosphere was cooled to −40°C., titanium tetrachloride (2.06 mL, 18.8 mmol) was added, and themixture was stirred for 5 min. Diisopropylethylamine (3.27 mL, 18.8mmol) was added, and the reaction was stirred at −40° C. for 5 min,giving a deep red homogeneous solution. A solution of the product ofExample 8 (4.81 g, 18.8 mmol) in dichloromethane (3 mL) was added, themixture was stirred for 15 min at −40° C. The reaction was quenched bythe addition of satd aq ammonium chloride solution, warmed to roomtemperature, and the organic phase was dried and evaporated.Chromatography of the residue on silica gel gave the 4R-isomer (1.9 g,25%) and the 4S-isomer (2.3 g, 30%) of the title compound.

4R-isomer ¹H NMR (CDCl₃, 300 MHz): δ 1.45-1.69 (m, 5H), 1.77-1.85 (m,2H), 2.05-2.15 (m, 3H), 2.95 (br s, 1H), 3.30 (dd, J=9, 12, 1H), 3.38(dd, J=2, 12, 1H), 3.60 (dd, J=2, 9, 1H), 3.79 (s, 3H), 4.21 (m, 1H),4.34 (d, J=14, 1H), 4.43 (br m, 1H), 4.96-5.07 (m, 2H), 5.07 (d, J=14,1H), 5.49 (s, 1H), 5.83 (m, 1H), 6.84 (d, J=9, 2H), 7.18 (d, J=9, 2H).4S-isomer ¹H NMR (CDCl₃, 300 MHz): δ 1.20 (m, 1H), 1.46-1.68 (m, 6H),2.04-2.16 (m, 2H), 2.22-2.31 (m, 1H), 3.31 (dd, J=9, 12, 1H), 3.39 (dd,J=2, 12, 1H), 3.54 (dd, J=2, 9, 1H), 3.81 (s, 3H), 3.90 (m, 1H), 4.13(m, 1H), 4.28 (d, J=14, 1H), 4.99-5.03 (m, 2H), 5.16 (d, J=14, 1H), 5.84(m, 1H), 6.86 (d, J=9, 2H), 7.18 (d, J=9, 2H).

Example 10

(R)-4-((2R,4S,6R)-2,4-Dihydroxy-6-((S)-3-methylpent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 9, with the modification that(3R,6S)-6-methyl-3-(triethylsilyloxy)oct-7-enal was substituted for(R)-3-(triethylsilyloxy)oct-7-enal, afforded the title compound.

Example 11

(R)-4-((2R,4R,6R)-2,4-Dihydroxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneand(R)-4-((2R,4S,6R)-2,4-Dihydroxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 9, with the modification that(R)-5-phenyl-3-(triethylsilyloxy)pentanal was substituted for(R)-3-(triethylsilyloxy)oct-7-enal, affords the title compounds.

Example 12

(R)-4-((2R,4R,6R)-6-Ethyl-2,4-dihydroxy-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 9, with the modification that(R)-3-(tert-butyldimethylsilyloxy)pentanal was substituted for(R)-3-(triethylsilyloxy)oct-7-enal, afforded the title compound afteracid treatment of the intermediate silylated aldol product.

Example 13

(R)-4-((2R,4S,6R)-4-Hydroxy-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

The title compound from Example 9, 4S-isomer (606 mg, 1.49 mmol) wasdissolved in toluene (31.5 mL) and methanol (6.02 mL), and a catalyticamount of 10-camphorsulfonic acid (105 mg) was added. The resultinghomogeneous solution was stirred at room temperature under a nitrogenatmosphere for 3 hours. The reaction was quenched with satd aq NaHCO₃(20 mL), extracted with 1:1 ethyl acetate/heptane, dried, andconcentrated. Chromatography of the residue on silica gel gave the titlecompound (522 mg, 83%) as an oil.

¹H NMR (CDCl₃, 300 MHz): δ 1.20 (m, 1H), 1.48-1.59 (m, 4H), 1.61-1.74(m, 2H), 2.01 (m, 1H), 2.12-2.26 (m, 2H), 3.07 (s, 3H), 3.23-3.28 (m,2H), 3.60 (m, 1H), 3.81 (s, 3H), 3.83-3.87 (m, 1H), 4.04-4.12 (m, 1H),4.24 (d, J=14, 1H), 5.01-5.15 (m, 3H), 5.86 (m, 1H), 6.87 (d, J=9, 2H),7.22 (d, J=9, 2H).

Example 14

(R)-4-((2R,4R,6R)-4-Hydroxy-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 13, with the modificationthat(R)-4-((2R,4R,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

Example 15

(R)-4-((2R,4S,6R)-4-Hydroxy-2-methoxy-6-((S)-3-methylpent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 13, with the modificationthat(R)-4-((2R,4S,6R)-2,4-dihydroxy-6-((S)-3-methylpent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

Example 16

(R)-4-((2R,4R,6R)-4-Hydroxy-2-methoxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 13, with the modificationthat(R)-4-((2R,4R,6R)-2,4-dihydroxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneis substituted for(R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 17

(R)-4-((2R,4S,6R)-4-Hydroxy-2-methoxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 13, with the modificationthat(R)-4-((2R,4S,6R)-2,4-dihydroxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneis substituted for(R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 18

(R)-4-((2R,4R,6R)-6-Ethyl-4-hydroxy-2-methoxy-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 13, with the modificationthat(R)-4-((2R,4R,6R)-6-ethyl-2,4-dihydroxy-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

Example 19

Methyl Hept-6-en-2-ynoate

A solution of allylmagnesium bromide (1M, 150 mL, 150 mmol) in etherunder a nitrogen atmosphere was cooled to −10° C., and propargylchloride (5.4 mL, 75 mmol) was added dropwise. The solution was stirredfor 24 h at room temperature, and then cooled to 0° C. Methylchloroformate was added dropwise, and the solution was allowed to stirat room temperature for 4 h. The reaction was quenched by cautiousaddition of satd aq NH₄Cl (100 mL) at 0° C. The organic layer was washedwith brine, dried, and evaporated to a residue. Chromatography on silicagel provided the title compound (4.5 g, 44%) as a pale yellow liquid.

¹H NMR (CDCl₃, 300 MHz): δ 2.36 (q, J=7 Hz, 2H), 2.46 (t, J=7 Hz, 2H),3.79 (s, 3H), 5.08-5.17 (m, 2H), 5.80-5.92 (m, 1H).

Example 20

(Z)-Methyl 3-Methylhepta-2,6-dienoate

A suspension of copper(I) iodide (12.38 g, 65 mmol) in 150 mL of dry THFunder a nitrogen atmosphere was cooled to −20° C., and methyllithium(1.6 M in ether, 81.5 mL, 130 mmol) was added dropwise over 15 min. Thesolution was cooled to −78° C., and 4.49 g (32.5 mmol) of the compoundfrom Example 19 in 15 mL of dry THF was added gradually, keeping thetemperature below −70° C. After 1 h, 40 mL of ethanol was addedcautiously, and the mixture was allowed to warm to room temperature. Themixture was diluted with ether, and washed with satd aq NH₄Cl (200 mL),5N NH₃ (4×250 mL), water (200 mL), and brine (200 mL), dried, and thebulk of the solvent was evaporated to give the title compound (6.8 g,100%) as an oil. The material had only minor solvent contamination andwas adequate for use in the next reaction.

¹H NMR (CDCl₃, 300 MHz): δ 1.92 (s, 3H), 2.26 (q, J=7 Hz, 2H), 2.76 (t,J=7 Hz, 2H), 3.71 (s, 3H), 4.98-5.10 (m, 2H), 5.71 (s, 1H), 5.80-5.92(m, 1H).

Example 21

(Z)-3-Methylhepta-2,6-dienoic Acid

A solution of the title compound from Example 20 (6.8 g, 32.5 mmol) inTHF (150 mL) was treated with 1 N LiOH (100 mL) and water (125 mL) andstirred vigorously for 4 days. The mixture was diluted with water andwashed twice with ether. The aqueous phase was taken to pH 1.5 byaddition of 2N HCl and extracted three times with ether. The organicextracts were dried and the solvents evaporated to give the titlecompound (2.57 g, 56%) as a pale yellow oil.

¹H NMR (CDCl₃, 300 MHz): δ 1.96 (s, 3H), 2.27 (q, J=8 Hz, 2H), 2.77 (t,J=8 Hz, 2H), 5.02-5.10 (m, 2H), 5.74 (s, 1H), 5.80-5.92 (m, 1H).

Example 22

(2R,4S,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-ylTrifluoromethanesulfonate

To a 50 mL dry flask with Nitrogen and a stir bar was added the titlecompound from Example 13 (500 mg, 1.19 mmol), 2,6-lutidine (0.687 mL,5.93 mmol), and dichloromethane (15 mL). After being cooled down to −11°C., trifluoromethanesulfonic anhydride (0.399 mL, 2.37 mmol) was addeddropwise via a syringe. The resulted homogeneous solution was stirred atthat temperature for 30 minutes. The reaction was quenched with 10% aqcitric acid (4 mL), extracted twice with dichloromethane, and dried overNa₂SO₄. and concentrated. Evaporation of the solvent gave the titlecompound as an oil, which was used in the next reaction without anyfurther purification.

Example 23

(Z)-((2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-Methylhepta-2,6-dienoate

A 100 mL dry flask under a nitrogen atmosphere was charged with NaH (60%in mineral oil, 186 mg, 4.65 mmol). The NaH was washed with pentane (5mL), THF (2 mL) was added, and the reaction was cooled to 0° C. Thetitle compound from Example 21 (651 mg, 4.65 mmol) in THF (3 mL) wasadded dropwise, after which 15-crown-5 (1.41 mL, 7.12 mmol) was added.The reaction was allowed to warm to room temperature and stirred for 10minutes, and then was cooled to 0° C. again. A solution of the titlecompound from Example 22 (1.19 mmol, used directly from the previousreaction) in THF (2 mL) was added, and the reaction was stirred at roomtemperature overnight.

The reaction was quenched with satd aq NH₄Cl (10 mL), extracted with 1:1ethyl acetate/heptane, dried over Na₂SO₄, and concentrated.Chromatography of the residue on silica gel first with 1/4 ethylacetate/heptane and then with 3/97 ethyl acetate/dichloromethane gavethe title compound as an oil (387 mg, 60%).

¹H NMR (CDCl₃, 300 MHz): δ 1.45-1.96 (m, 7H), 1.90 (d, J=1, 3H),2.09-2.20 (m, 3H), 2.21-2.28 (m, 2H), 2.75 (t, J=8, 2H), 3.12 (s, 3H),3.21-3.27 (m, 2H), 3.80-3.89 (m, 1H), 3.82 (s, 3H), 3.93 (m, 1H), 4.28(d, J=14, 1H), 4.96-5.13 (m, 5H), 5.21 (br m, 1H), 5.70 (s, 1H),5.78-5.93 (m, 1H), 6.87 (d, J=9, 2H), 7.22 (d, J=9, 2H).

Example 24

(2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl3-Methylbut-2-enoate

Application of the method shown in Example 23, with the modificationthat 3-methyl-2-butenoic acid is substituted for(Z)-3-methylhepta-2,6-dienoic acid, affords the title compound.

Example 25

(2Z,6E)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-Methylnona-2,6,8-trienoate

Application of the method shown in Example 23, with the modificationthat (2Z,6E)-3-methylnona-2,6,8-trienoic acid is substituted for(Z)-3-methylhepta-2,6-dienoic acid, affords the title compound.

Example 26

(Z)-((2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-((S)-3-methylpent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-Methylhepta-2,6-dienoate

Triflate formation using the method shown in Example 22, with themodification that(R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-((S)-3-methylpent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,followed by triflate displacement using the method shown in Example 23,afforded the title compound.

Example 27

(Z)-((2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl)3-Methylhepta-2,6-dienoate

Triflate formation using the method shown in Example 22, with themodification that(R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneis substituted for(R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,followed by triflate displacement using the method shown in Example 23,affords the title compound.

Example 28

(2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl3-Methylbut-2-enoate

Triflate formation using the method shown in Example 22, with themodification that(R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneis substituted for(R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,followed by triflate displacement using the method shown in Example 23,with the modification that 3-methyl-2-butenoic acid is substituted for(Z)-3-methylhepta-2,6-dienoic acid, affords the title compound.

Example 29

(2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-ylBenzoate

To a solution of benzoic acid (31.7 mg, 0.260 mmol) in dry toluene (5mL) under a nitrogen atmosphere was added diisopropylethylamine (0.0435mL, 0.250 mmol) and 2,4,6-trichlorobenzoyl chloride (0.0391 mL, 0.250mmol). The mixture was stirred at room temperature for 3 h, after whichthe title compound from Example 14 (21.5 mg, 0.051 mmol) and DMAP (32.9mg, 0.269 mmol) were added. This mixture was stirred at room temperaturefor 18 h, after which it was diluted with ether and washed with satd aqNH₄Cl and brine, and the organic phase was dried and evaporated.Chromatography of the residue on silica gel, eluting with an ethylacetate/dichloromethane gradient, afforded the title compound (21.7 mg,81%) as an oil.

Example 30

(2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl4-Methoxybenzoate

Application of the method shown in Example 29, with the modificationthat 4-methoxybenzoic acid was substituted for benzoic acid, affordedthe title compound.

Example 31

(2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl4-(Methylsulfonyl)benzoate

Application of the method shown in Example 29, with the modificationthat 4-methylsulfonylbenzoic acid was substituted for benzoic acid,afforded the title compound.

Example 32

(2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-ylHept-6-enoate

Application of the method shown in Example 29, with the modificationthat 6-heptenoic acid was substituted for benzoic acid, afforded thetitle compound.

Example 33

(2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-ylOct-7-enoate

Application of the method shown in Example 29, with the modificationthat 6-octenoic acid was substituted for benzoic acid, afforded thetitle compound.

Example 34

(2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-ylBenzoate

Application of the method shown in Example 29, with the modificationthat(R)-4-((2R,4R,6R)-4-hydroxy-2-methoxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneis substituted for(R)-4-((2R,4R,6R)-4-hydroxy-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 35

(2R,4R,6R)-6-Ethyl-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-tetrahydro-2H-pyran-4-ylBenzoate

Application of the method shown in Example 29, with the modificationthat(R)-4-((2R,4R,6R)-6-ethyl-4-hydroxy-2-methoxy-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((2R,4R,6R)-4-hydroxy-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

Example 36

(R)-4-((1R,4Z,8Z,13R,15R)-15-Methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneand(R)-4-((1R,4Z,8E,13R,15R)-15-Methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

To a 250 mL dry flask was added the title compound from Example 23 (387mg, 0.712 mmol) and dichloromethane (70 mL). Nitrogen was bubbledthrough the mixture for 30 minutes to degas the solution. The bubblingwas continued while the solution was heated briefly to reflux and thencooled to room temperature. The bubbling was stopped, a solution ofsecond generation Grubbs catalyst (30.2 mg, 0.036 mmol) indichloromethane (4 mL), was added, and the reaction was stirred at roomtemperature for 14 hours. The reaction was then quenched by the additionof DMSO (0.1 mL) followed by stirring open to the atmosphere for 24hours. Concentration of the mixture and chromatography of the residue onsilica gel, eluting with 3/49/49 ethyl acetate/dichloromethane/heptanegave the title compound (290 mg, 79%) as a 1:1 mixture of its E- andZ-isomers, as an white solid.

The mixture of E- and Z-isomers was separated through supercriticalfluid chromatography (SFC) on a CHIRALPAK AS-H column. Concentrationgave the individual title compounds as white solids.

8Z-isomer ¹H NMR (CDCl₃, 300 MHz): δ 1.20-1.35 (m, 3H), 1.42-1.74 (m,5H), 1.80-1.92 (m, 2H), 1.92 (s, 3H), 2.20-2.32 (m, 3H), 2.88 (m, 1H),3.08 (s, 3H), 3.14-3.24 (m, 2H), 3.74-3.81 (m, 1H), 3.81 (s, 3H),4.21-4.29 (m, 1H), 4.30 (d, J=14, 1H), 5.08 (d, J=14, 1H), 5.26 (m, 1H),5.42 (m, 2H), 5.65 (s, 1H), 6.87 (d, J=9, 2H), 7.24 (d, J=9, 2H).8E-isomer ¹H NMR (CDCl₃, 300 MHz): δ 1.21-1.44 (m, 3H), 1.54-1.78 (m,5H), 1.83-2.07 (m, 2H), 1.90 (s, 3H), 2.08-2.41 (m, 3H), 3.11 (s, 3H),3.14-3.25 (m, 3H), 3.69-3.81 (m, 1H), 3.82 (s, 3H), 4.29 (d, J=14, 1H),4.51 (m, 1H), 5.08 (d, J=14, 1H), 5.22 (m, 1H), 5.46 (m, 2H), 6.23 (s,1H), 6.87 (d, J=9, 2H), 7.24 (d, J=9, 2H).

Example 37

(R)-4-((1R,4Z,8Z,10S,13R,15R)-15-Methoxy-5,10-dimethyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneand(R)-4-((1R,4Z,8E,10S,13R,15R)-15-Methoxy-5,10-dimethyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 36, with the modificationthat(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-((S)-3-methylpent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate was substituted for(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate, afforded the title compounds.

Example 38

(R)-4-((1R,4Z,8E,10Z,15R,17R)-17-Methoxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadeca-4,8,10-trien-17-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneand(R)-4-((1R,4Z,8E,10E,15R,17R)-17-Methoxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadeca-4,8,10-trien-17-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 36, with the modificationthat(2Z,6E)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylnona-2,6,8-trienoate is substituted for(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate, affords the title compounds.

Example 39

(R)-4-((1R,13R,15R,Z)-15-Methoxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-8-en-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneand(R)-4-((1R,13R,15R,E)-15-Methoxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-8-en-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 36, with the modificationthat(2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-ylhept-6-enoate was substituted for(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate, afforded the title compounds.

Example 40

(R)-4-((1R,14R,16R,Z)-16-Methoxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadec-9-en-16-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneand(R)-4-((1R,14R,16R,E)-16-Methoxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadec-9-en-16-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 36, with the modificationthat(2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yloct-7-enoate was substituted for(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate, afforded the title compounds.

Example 41

(R)-4-((1R,13R,15R,Z)-15-Methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-4-en-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

A solution of the title compound from Example 36 (12.4 mg, 0.024 mmol, amixture of E- and Z-isomers) in ethanol (1 mL) and ethyl acetate (3 mL)was flushed with nitrogen, and 10% Pd/C (8.1 mg) was added as a slurryin a small volume of water. The atmosphere was replaced with hydrogen,and the mixture was stirred for 22 h. The mixture was filtered andevaporated. Chromatography of the residue on a C18 reversed phasecolumn, eluting with acetonitrile/water, afforded the title compound(5.0 mg, 40%) as a solid.

Example 42

(R)-4-((1R,13R,15R)-15-Methoxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadecan-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 41, with the modificationthat(R)-4-((1R,13R,15R,Z)-15-methoxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-8-en-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((1R,4Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

Example 43

(R)-4-((1R,14R,16R)-16-Methoxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadecan-16-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 41, with the modificationthat(R)-4-((1R,14R,16R,E)-16-methoxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadec-9-en-16-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((1R,4Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

Example 44

(R)-4-((1R,15R,17R,Z)-17-Methoxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadec-4-en-17-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

Application of the method shown in Example 41, with the modificationthat(R)-4-((1R,4Z,8E,10Z,15R,17R)-17-methoxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadeca-4,8,10-trien-17-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneis substituted for(R)-4-((1R,4Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 45

(Z)-((2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-pentyl-tetrahydro-2H-pyran-4-yl)3-Methylhept-2-enoate

Application of the method shown in Example 41, with the modificationthat(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate is substituted for(R)-4-((1R,4Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 46

(R)-4-((1R,4Z,8Z,13R,15R)-15-Hydroxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)thiazolidin-2-one,Compound 8

To a solution of the title compound from Example 36, 8Z-isomer (13.3 mg,0.026 mmol) in acetonenitrile (0.266 mL) was added a solution of cericammonium nitrate (36 mg, 0.064 mmol) in water (0.133 mL). The reactionwas stirred at room temperature for 2 hours, after which the mixture wasdiluted with dichloromethane, washed with satd aq NaHCO₃, and theorganic phase was dried and concentrated. Chromatography of the residueon silica gel eluting with an ethyl acetate/heptane gradient gave thetitle compound (6.2 mg, 63%) of as a white solid.

¹H NMR (CDCl₃, 300 MHz): δ 1.22-1.34 (m, 2H), 1.38-1.61 (m, 3H),1.75-1.85 (m, 2H), 1.93 (s, 3H), 2.00-2.14 (m, 2H), 2.20-2.28 (m, 3H),2.31-2.46 (m, 1H), 2.49-2.62 (m, 1H), 3.36-3.50 (m, 2H), 3.65 (br s,1H), 3.82 (m, 1H), 4.28 (m, 1H), 5.26-5.41 (m, 2H), 5.46 (m, 1H), 5.69(m, 2H).

Example 47

(R)-4-((1R,4Z,8E,13R,15R)-15-Hydroxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)thiazolidin-2-one,Compound 8a

Application of the method shown in Example 46, with the modificationthat(R)-4-((1R,4Z,8E,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 1.25-1.48 (m, 3H), 1.56-1.77 (m, 3H), 1.89(d, J=1 Hz, 3H), 2.01-2.12 (m, 3H), 2.13-2.25 (m, 3H), 2.46 (quin, J=6Hz, 1H), 2.75 (dt, J=12, 8 Hz, 1H), 3.40 (dd, J=6, 12 Hz, 1H), 3.49 (dd,J=9, 12 Hz, 1H), 3.82 (dd, J=6, 9 Hz, 1H), 3.94 (br s, 1H), 4.40 (m,1H), 5.30-5.48 (m, 3H), 5.66 (s, 1H), 5.72 (s, 1H).

Example 48

(R)-4-((1R,4Z,8E,10S,13R,15R)-15-Hydroxy-5,10-dimethyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)thiazolidin-2-one,Compound 8b

Application of the method shown in Example 46, with the modificationthat(R)-4-((1R,4Z,8E,10S,13R,15R)-15-methoxy-5,10-dimethyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 0.96 (d, J=7 Hz, 3H), 1.20-1.47 (m, 3H),1.55-1.68 (m, 3H), 1.89 (d, J=1 Hz, 3H), 2.01-2.17 (m, 3H), 2.22-2.35(m, 2H), 2.39-2.48 (m, 1H), 2.64-2.72 (m, 1H), 3.40 (dd, J=6, 12 Hz,1H), 3.49 (dd, J=9, 12 Hz, 1H), 3.82 (dd, J=6, 9 Hz, 1H), 4.04 (s, 1H),4.35 (m, 1H), 5.22-5.39 (m, 3H), 5.67 (s, 1H), 5.75 (s, 1H).

Example 49

(R)-4-((1R,4Z,8E,10Z,15R,17R)-17-Hydroxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadeca-4,8,10-trien-17-yl)thiazolidin-2-one,Compound 9

Application of the method shown in Example 46, with the modificationthat(R)-4-((1R,4Z,8E,10Z,15R,17R)-17-methoxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadeca-4,8,10-trien-17-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneis substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 50

(R)-4-((1R,13R,15R,Z)-15-Hydroxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-8-en-15-yl)thiazolidin-2-one,Compound 10a

Application of the method shown in Example 46, with the modificationthat(R)-4-((1R,13R,15R,Z)-15-methoxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-8-en-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 1.30-1.75 (m, 8H), 1.75-2.10 (m, 6H),2.15-2.50 (m, 3H), 2.55-2.65 (m, 1H), 3.41 (dd, J=6, 12 Hz, 1H), 3.52(dd, J=9, 12 Hz, 1H), 3.87 (dd, J=6, 9 Hz, 1H), 4.11 (m, 1H), 4.25 (brs, 1H), 5.23 (m, 1H), 5.41 (m, 2H), 5.62 (br s, 1H).

Example 51

(R)-4-((1R,14R,16R,E)-16-Hydroxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadec-9-en-16-yl)thiazolidin-2-one,Compound 10c

Application of the method shown in Example 46, with the modificationthat(R)-4-((1R,14R,16R,E)-16-methoxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadec-9-en-16-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 1.17-1.51 (m, 8H), 1.56-1.73 (m, 4H),1.91-2.08 (m, 5H), 2.25-2.46 (m, 3H), 3.43 (dd, J=6, 12 Hz, 1H), 3.51(dd, J=9, 12 Hz, 1H), 3.87 (dd, J=6, 8 Hz, 1H), 4.14 (m, 1H), 4.35 (s,1H), 5.29 (m, 1H), 5.31-5.46 (m, 2H), 5.82 (s, 1H).

Example 52

(R)-4-((1R,13R,15R,Z)-15-Hydroxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-4-en-15-yl)thiazolidin-2-one,Compound 10

Application of the method shown in Example 46, with the modificationthat(R)-4-((1R,13R,15R,Z)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-4-en-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 1.01-1.35 (m, 5H), 1.47-1.75 (m, 8H), 1.86(d, J=1 Hz, 3H), 1.98-2.17 (m, 3H), 2.35-2.40 (m, 1H), 3.07-3.17 (m,1H), 3.40 (dd, J=6, 12 Hz, 1H), 3.51 (dd, J=9, 12 Hz, 1H), 3.85 (m, 1H),4.14 (m, 1H), 4.37 (br s, 1H), 5.32 (m, 1H), 5.62 (s, 1H), 5.73 (s, 1H).

Example 53

(R)-4-((1R,15R,17R,Z)-17-Hydroxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadec-4-en-17-yl)thiazolidin-2-one,Compound 11

Application of the method shown in Example 46, with the modificationthat(R)-4-((1R,15R,17R,Z)-17-methoxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadec-4-en-17-yl)-3-(4-methoxybenzyl)thiazolidin-2-oneis substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 54

(R)-4-((1R,13R,15R)-15-Hydroxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadecan-15-yl)thiazolidin-2-one,Compound 10b

Application of the method shown in Example 46, with the modificationthat(R)-4-((1R,13R,15R)-15-methoxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadecan-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 1.23-1.48 (m, 8H), 1.48-1.72 (m, 8H), 1.79(m, 1H), 1.93-2.09 (m, 3H), 2.32-2.42 (m, 1H), 2.49-2.58 (m, 1H), 3.40(dd, J=6, 12 Hz, 1H), 3.52 (dd, J=9, 12 Hz, 1H), 3.86 (dd, J=6, 9 Hz,1H), 4.19 (m, 1H), 4.32 (br s, 1H), 5.40 (m, 1H), 5.66 (s, 1H).

Example 55

(R)-4-((1R,14R,16R)-16-Hydroxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadecan-16-yl)thiazolidin-2-one,Compound 10d

Application of the method shown in Example 46, with the modificationthat(R)-4-((1R,14R,16R)-16-methoxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadecan-16-yl)-3-(4-methoxybenzyl)thiazolidin-2-onewas substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 0.85 (m, 2H), 1.23-1.42 (m, 8H), 1.46-1.71(m, 9H), 1.96-2.07 (m, 3H), 2.40 (t, J=6 Hz, 2H), 3.40 (dd, J=6, 12 Hz,1H), 3.52 (dd, J=9, 12 Hz, 1H), 3.85 (dd, J=6, 9 Hz, 1H), 4.11 (m, 1H),4.34 (s, 1H), 5.40 (m, 1H), 5.68 (s, 1H).

Example 56

(Z)-((2R,4R,6R)-2-Hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-Methylhepta-2,6-dienoate, Compound 1

Application of the method shown in Example 46, with the modificationthat(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate was substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 1.41-1.55 (m, 6H), 1.85-1.96 (m, 2H), 1.94(d, J=1 Hz, 3H), 2.07 (quar, J=7 Hz, 2H), 2.25 (quar, J=7 Hz, 2H), 2.76(dt, J=2, 8 Hz, 2H), 3.39 (dd, J=6, 12 Hz, 1H), 3.50 (dd, J=9, 12 Hz,1H), 3.84 (m, 1H), 4.03 (m, 1H), 4.31 (s, 1H), 4.96-5.09 (m, H), 5.42(m, 1H), 5.60 (s, 1H), 5.69 (s, 1H), 5.75-5.89 (m, 2H).

Example 57

(2R,4R,6R)-2-Hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl3-Methylbut-2-enoate, Compound 3

Application of the method shown in Example 46, with the modificationthat(2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl3-methylbut-2-enoate is substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 58

(Z)-((2R,4R,6R)-2-Hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl)3-Methylhepta-2,6-dienoate, Compound 5

Application of the method shown in Example 46, with the modificationthat(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate is substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 59

(2R,4R,6R)-2-Hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl3-Methylbut-2-enoate, Compound 6

Application of the method shown in Example 46, with the modificationthat(2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-yl3-methylbut-2-enoate is substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 60

(2R,4R,6R)-2-Hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-ylBenzoate, Compound 4

Application of the method shown in Example 46, with the modificationthat(2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-ylbenzoate was substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 1.40-1.63 (m, 6H), 1.99-2.09 (m, 4H), 3.41(dd, J=6, 12 Hz, 1H), 3.51 (dd, J=9, 12 Hz, 1H), 3.84 (dd, J=6, 9 Hz,1H), 3.90 (s, 1H), 4.17 (m, 1H), 4.94-5.04 (m, 2H), 5.63 (m, 1H), 5.68(s, 1H), 5.79 (m, 1H), 7.48 (t, J=7 Hz, 2H), 7.61 (t, J=8 Hz, 1H), 7.99(d, J=7 Hz, 2H).

Example 61

(2R,4R,6R)-2-Hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl4-Methoxybenzoate, Compound 4a

Application of the method shown in Example 46, with the modificationthat(2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl4-methoxybenzoate was substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 1.39-1.63 (m, 6H), 1.96-2.13 (m, 4H), 3.41(dd, J=6, 12 Hz, 1H), 3.50 (dd, J=9, 12 Hz, 1H), 3.83-3.87 (m, 1H), 3.88(s, 3H), 4.01 (s, 1H), 4.16 (m, 1H), 4.94-5.04 (m, 2H), 5.61 (m, 1H),5.66 (s, 1H), 5.78 (m, 1H), 6.95 (d, J=9 Hz, 2H), 7.94 (d, J=9 Hz, 2H).

Example 62

(2R,4R,6R)-2-Hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl4-(Methylsulfonyl)benzoate, Compound 4b

Application of the method shown in Example 46, with the modificationthat(2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl4-(methylsulfonyl)benzoate was substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 1.40-1.66 (m, 5H), 1.98-2.18 (m, 5H), 3.08(s, 3H), 3.20 (m, 1H), 3.41 (dd, J=6, 12 Hz, 1H), 3.50 (dd, J=9, 12 Hz,1H), 3.81 (dd, J=6, 9 Hz, 1H), 4.22 (m, 1H), 4.95-5.04 (m, 2H), 5.60 (m,1H), 5.74-5.83 (m, 2H), 8.04 (d, J=9 Hz, 2H), 8.23 (d, J=9 Hz, 2H).

Example 63

(2R,4R,6R)-2-Hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-ylBenzoate, Compound 7

Application of the method shown in Example 46, with the modificationthat(2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-phenethyl-tetrahydro-2H-pyran-4-ylbenzoate is substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 64

(2R,4R,6R)-6-Ethyl-2-hydroxy-2-((R)-2-oxothiazolidin-4-yl)-tetrahydro-2H-pyran-4-ylBenzoate, Compound 7a

Application of the method shown in Example 46, with the modificationthat(2R,4R,6R)-6-ethyl-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-tetrahydro-2H-pyran-4-ylbenzoate was substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 0.94 (t, J=7 Hz, 3H), 1.49-1.63 (m, 3H),1.93-2.16 (m, 3H), 3.43 (dd, J=6, 11 Hz, 1H), 3.51 (dd, J=8, 11 Hz, 1H),3.79-3.92 (m, 2H), 4.10 (m, 1H), 5.64 (m, 1H), 5.87 (s, 1H), 7.48 (t,J=7 Hz, 2H), 7.61 (t, J=6 Hz, 1H), 8.00 (d, J=7 Hz, 2H).

Example 65

(Z)-((2R,4R,6R)-2-Hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-pentyl-tetrahydro-2H-pyran-4-yl)3-Methylhept-2-enoate, Compound 2

Application of the method shown in Example 46, with the modificationthat(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-pentyl-tetrahydro-2H-pyran-4-yl)3-methylhept-2-enoate is substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 66

(R)-4-((2R,4R,6R)-4-Azido-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

A solution of the title compound from Example 22 (1.19 mmol, useddirectly from the previous reaction) in DMF (12 mL) was treated withsodium azide (400 mg, 6.15 mmol), and the mixture was stirred at roomtemperature for 22 h. The reaction mixture was diluted with ethylacetate, washed with satd aq NaHCO₃, ice cold 5% aq citric acid, andbrine, and the organic phase was dried and concentrated. Chromatographyof the residue on silica gel eluting with dichloromethane/ethyl acetategave the title compound (432 mg, 82%) as an oil.

Example 67

(R)-4-((2R,4R,6R)-4-Amino-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one

A suspension of the title compound from Example 66 (432 mg, 0.967 mmol)in ethanol (3 mL) and water (1 mL) was treated with NH₄Cl (122 mg, 2.27mmol) and zinc dust (85.4 mg, 1.30 mmol), and the mixture was stirredvigorously at room temperature. After 6 h, an additional portion of zinc(100 mg) and NH₄Cl (127 mg) was added, together with additional ethanol(4.5 mL) and water (1.5 mL), and stirring was continued for 18 h. Oncemore portions of zinc (100 mg) and NH₄Cl (124 mg) were added, andstirring was continued. After 4 h, the mixture was diluted with ethylacetate, washed with half-concentrated NH₄OH and brine, dried, andconcentrated. The residue was treated with NH₄Cl (200 mg) in methanol(20 mL), and this mixture was allowed to stir at room temperature for 2days. The mixture was diluted with ethyl acetate, washed with 1/1-satdaq NaHCO₃/brine and then with brine, dried, and concentrated.Chromatography of the residue on silica gel eluting withmethanol/dichloromethane gave the title compound (305 mg, 75%) as anoil.

Example 68

(Z)-N-((2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)-3-methylhepta-2,6-dienamide

A solution of the title compound from Example 67 (155 mg, 0.368 mmol) indichloromethane (5 mL) was treated with the title compound from Example21 (58 mg, 0.42 mmol), HOBT (65 mg, 0.42 mmol), and EDC (78 mg, 0.41mmol), and the mixture was stirred at room temperature for 4 days. Themixture was then concentrated and the residue was chromatographed onsilica, eluting with ethyl acetate/hexanes, which afforded the titlecompound (133 mg, 67%) as a crystalline solid.

Example 69

(1R,4Z,8Z,13R,15R)-15-Methoxy-15-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-5-methyl-14-oxa-2-aza-bicyclo[11.3.1]heptadeca-4,8-dien-3-oneand(1R,4Z,8E,13R,15R)-15-Methoxy-15-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-5-methyl-14-oxa-2-aza-bicyclo[11.3.1]heptadeca-4,8-dien-3-one

Application of the method shown in Example 36, with the modificationthat(Z)-N-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)-3-methylhepta-2,6-dienamidewas substituted for(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate, afforded the title compounds.

Example 70

Pent-4-enyl(2R,4R,6R)-2-Methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-ylcarbamate

A solution of the title compound from Example 67 (113 mg, 0.269 mmol) indichloromethane (2 mL) was treated with a solution of 4-nitrophenylpent-4-enyl carbonate (88 mg, 0.35 mmol) in dichloromethane (0.8 mL),diisopropylethylamine (0.061 mL, 0.35 mmol), and a catalytic amount ofDMAP (0.2 mg). The mixture was stirred for 24 h, after which it waschromatographed directly on silica gel, eluting with ethylacetate/dichloromethane, to give the title compound (119 mg, 83%) as anoil.

Example 71

(1R,13R,15R,Z)-15-Methoxy-15-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-4,14-dioxa-2-aza-bicyclo[11.3.1]heptadec-8-en-3-oneand(1R,13R,15R,E)-15-Methoxy-15-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-4,14-dioxa-2-aza-bicyclo[11.3.1]heptadec-8-en-3-one

Application of the method shown in Example 36, with the modificationthat pent-4-enyl(2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-ylcarbamatewas substituted for(Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)3-methylhepta-2,6-dienoate, afforded the title compounds.

Example 72

(1R,4Z,8Z,13R,15R)-15-Hydroxy-5-methyl-15-((R)-2-oxothiazolidin-4-yl)-14-oxa-2-aza-bicyclo[11.3.1]heptadeca-4,8-dien-3-one,Compound 8c

Application of the method shown in Example 46, with the modificationthat(1R,4Z,8Z,13R,15R)-15-methoxy-15-(((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-5-methyl-14-oxa-2-aza-bicyclo[11.3.1]heptadeca-4,8-dien-3-onewas substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound, together with the 8E-isomer.

¹H NMR (CDCl₃, 300 MHz): δ 1.30-1.95 (m, 7H), 1.78 (s, 3H), 1.80-2.60(m, 7H), 3.40-3.51 (m, 3H), 3.77 (m, 1H), 4.15-4.41 (m, 2H), 5.23-5.37(m, 2H), 5.77 and 5.79 (singlets, 1H), 6.12 and 6.14 (singlets, 1H),7.08 and 7.30 (doublets, J=8 Hz, 1H).

Example 73

(1R,13R,15R,Z)-15-Hydroxy-15-((R)-2-oxothiazolidin-4-yl)-4,14-dioxa-2-aza-bicyclo[11.3.1]heptadec-8-en-3-one,Compound 8d

Application of the method shown in Example 46, with the modificationthat(1R,13R,15R,Z)-15-methoxy-15-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-4,14-dioxa-2-aza-bicyclo[11.3.1]heptadec-8-en-3-oneis substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,affords the title compound.

Example 74

(Z)-N-((2R,4R,6R)-2-Hydroxy-2-((R)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)-3-methylhepta-2,6-dienamide,Compound 1a

Application of the method shown in Example 46, with the modificationthat(Z)-N-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)-3-methylhepta-2,6-dienamidewas substituted for(R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one,afforded the title compound.

¹H NMR (CDCl₃, 300 MHz): δ 1.35-1.74 (m, 6H), 1.79-1.88 (m, 2H), 1.83(s, 3H), 2.00-2.15 (m, 2H), 2.24 (guar, J=7 Hz, 2H), 2.55 (br s, 1H),2.62-2.79 (m, 2H), 3.38-3.52 (m, 2H), 3.68-3.81 (m, 1H), 4.01 (m, 1H),4.44 (m, 1H), 4.94-5.07 (m, 4H), 5.56 (s, 1H), 5.71-5.90 (m, 3H), 6.87(m, 1H).

Example 75 Actin Polymerization Inhibition Assay

The quantative effects of the test compounds on the kinetics of actinpolymerization were determined using a non-muscle actin polymerizationkit, Actin Polymerization Biochem Kit, according to the instructions ofthe manufacturer (Cytoskeleton Inc; Denver, Colo.). This assay evaluatesthe fluorescence intensity of pyrene actin, which is greater forpolymeric actin than for monomeric actin. The ability of the testcompounds to inhibit actin assembly was determined by measuring theirability to inhibit this increase in the fluorescence intensity of thepyrene-labeled actin. Results were expressed as the percent inhibitionmeasured at a standard test concentration of 10 uM.

Percent inhibition Compound at 10 uM 1 52.3  1a 32.4 4 52.0  4a 42.2  4b45.6 8 69.9  8a 67.2  8b 61.7  8c 44.9 10  44.1 10a 14.0 10b 21.8 10c21.7 10d 10.4

Example 76 NIH/3T3 Cell Morphology Assay

NIH/3T3 cells were grown in DMEM-H containing glutamine and 10% ColoradoCalf Serum. Cells were passaged regularly prior to reaching confluence.Eighteen to 24 hours prior to experimentation, the cells were platedonto Poly-L-Lysine-coated glass coverslips. On the day ofexperimentation, the cell culture medium was removed and was replacedwith medium containing from 10 nM to 100 uM of the test compound, andthe cells were incubated for 30 minutes at 37° C. The culture medium wasthen removed and the cells were washed with warmed PBS and fixed for 10minutes with warmed 4% paraformaldehyde. The cells were permeabilizedwith 0.5% Triton-X, stained with TRITC-conjugated phalloidin and imagedusing a Nikon Eclipse E600 epifluorescent microscope to determine thedegree of actin disruption. Results were expressed as the concentrationat which complete disruption of the actin cytoskeleton was observed.

Concentration giving complete actin Compound disruption, uM 8  5 8a 158b 25

The invention, and the manner and process of making and using it, arenow described in such full, clear, concise and exact terms as to enableany person skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the scope of the present invention as setforth in the claims. To particularly point out and distinctly claim thesubject matter regarded as invention, the following claims conclude thisspecification.

1. A compound of Formula II, or pharmaceutically-acceptable salts ortautomers thereof:

wherein: the ring containing X₁ is fully saturated: R_(a) is an alkylenechain, from 8-11 atoms in length, wherein the alkylene chain optionallycontains from 1 to 3 unsaturations, and is optionally substituted withalkyl; X₁=S; Y₁=NR₆; Y₂=O; Z₁=absent; Q₁ and Q₂ are O; A₁ and A₂ areindependently hydrogen, halo, alkyl, or alkoxy; n=2 or 3; and R₆ is H oralkyl.
 2. The compound according to claim 1, wherein A₁ and A₂ are bothhydrogen.
 3. The compound according to claim 1, wherein said compound isCompound 13, which is(S)-4-((1R,4Z,8Z,10S,13R,15R)-15-hydroxy-5,10-dimethyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-1,3-thiazinan-2-one.4. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and at least one compound according to claim
 3. 5. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and at least one compound according to claim
 1. 6. A method forreducing intraocular pressure, comprising the step of administering to asubject in need thereof a compound according to claim 1, in an amounteffective to alter actin cytoskeleton.